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.26 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.27
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.26,27,28,29 The risk of pneumococcal infection is greater in individuals with CD4+ T+ cell counts < 500/μL compared with > 500/μL, and is greatest with CD4+ T cell counts < 200/μL.29 Infection with S. pneumoniae with reduced sensitivity to penicillin occurs at a similar frequency in people with HIV infection and the general population.30
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%),31 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, meningitis32 pericarditis and endocarditis33 cervical cellulitis,34 and testicular abscess.35
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.26 Additional testing to be considered should include urine tests for pneumococcus and legionella antigen 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.26 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 with doxycycline 100mg orally 12 hourly for one week. In patients with penicillin allergy, doxycycline or clarithromycin may be used, or for parenteral therapy, moxifloxacin. In severe pneumonia, intravenous ceftriaxone 1 g daily (or benzyl penicillin 1.2 g every 4 hours with gentamicin) plus azithromycin 500 mg daily is recommended. Specific recommendations exist for tropical areas of northern Australia.36
Historically, 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.37,38 However, a randomised, placebo-controlled study in African adults showed no decrease in pneumococcal disease in the vaccinated group compared with the placebo group.39 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,40 and both combination antiretroviral therapy (cART) and vaccination with pneumococcal vaccine had independent protective effects against pneumococcal infection regardless of CD4+ T 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. 41 Since 2010, a 13-valent conjugate vaccine (PCV13) has been registered, which may offer additional protection. There is good evidence of immunogenicity and safety of this vaccine in patients with HIV infection 42, 43, 44 Most authorities would now therefore favour vaccination.42, 45 Current guidelines generally suggest the use of the conjugated polysaccharide vaccine first followed by the unconjugated polysaccharide vaccine 8 weeks or more later.42
Pneumocystis jiroveci pneumonia
Pneumocystis jiroveci (previously Pneumocystis carinii)46 is a fungus47 that is ubiquitous. It is unclear whether infection occurs as a primary event48 or as a result of colonisation with reactivation49 50, although antibodies against the organism are present in more than 85% of children under 3 years of age, suggesting that reactivation occurs following immunosuppression. P. jiroveci pneumonia is still the most common AIDS-defining condition and is usually seen in people presenting late in the course of HIV infection51 or in people with poor adherence to PJP prophylaxis or cART. P. jirovecii pneumonia occurs uncommonly in persons with a CD4+ T cell count > 200 cells/μL, or a proportion of CD4+ T cells that is > 14% of total lymphocytes, although cases have occasionally been reported in people with more preserved immune function.52
The major manifestation of P. jiroveci infection is PJP. The presentation of PJP is subacute with fever, a non-productive cough, chest tightness and dyspnoea. Symptoms may be present for 2 to 6 weeks or more before the diagnosis is made. Extrapulmonary manifestations are rare and require tissue biopsy for diagnosis.53 The typical clinical scenario of a patient with PJP is an immunodeficient person (CD4+ T cell count < 200/μL), who has not achieved suppression of HIV replication, is not taking cotrimoxazole prophylaxis, and presents with fatigue and fevers. The patient may not necessarily have noticed cough or dyspnoea, yet a non-productive cough is commonly apparent during the clinical assessment. Respiratory examination may reveal no signs aside from tachypnoea and oxygen desaturation on exertion, although crackles may be present on auscultation of the chest. Pneumothoraces may complicate severe PJP.
Pneumocystosis-associated immune reconstitution inflammatory syndrome
Pneumonitis and organising pneumonia may be seen as manifestations of an immune reconstitution inflammatory syndrome (IRIS) after cART is commenced and occur in approximately 4% of cases. Distinguishing a pneumonitis secondary to an IRIS after commencement of cART from undiagnosed PJP may be difficult.
The initial diagnostic approach to PJP includes consideration of the clinical likelihood of disease. People with advanced immunodeficiency who present with fever, fatigue and a dry cough have a high likelihood of PJP if they are not taking PJP prophylaxis, although other infections may present in such a manner. Other pathogens may cause respiratory disease (e.g. Mycobacterium tuberculosis, Mycobacterium avium complex, Streptococcus pneumoniae, Rhodococcus spp., Nocardia spp. and Cryptococcus neoformans) and these need to be considered in the differential diagnosis of any pulmonary presentation. It is especially important to consider the possibility of tuberculosis, as infection control and public health issues need to be considered.
The initial recommended investigation is a chest radiograph, which may reveal peri-hilar interstitial infiltrates or diffuse alveolar shadowing (Figure 1). The chest radiograph may be normal in more than 10% of cases.54 Additional focal pathology is suggestive of an alternative diagnosis. PJP may be complicated by pneumothoraces and pleural effusions are very rare. If pleural effusions are detected, other diagnoses should be considered. Even in cases with a normal chest radiograph, high resolution computed tomography (CT) of the chest (Figure 2) may reveal the typical ‘ground glass’ changes seen in the alveolitis due to PJP.55 Changes other than ground glass may occur but are less common.56
An expectorated sputum sample may be examined for P. jiroveci cysts by immunofluorescence (see below) but only has a sensitivity of approximately 55%.57 A more sensitive approach is the examination of an induced sputum specimen which is obtained by the induction of a deep cough after the inhalation of hypertonic saline.58,59 Pneumothorax should be excluded before sputum induction is undertaken. The procedure should be performed in an appropriately ventilated room, in case other pathogens are present. Induced sputum enables lower respiratory tract sampling, which is suitable for analysis for the presence of P. jiroveci cysts. An alternative to obtaining an induced sputum is bronchoscopy and bronchoalveolar lavage.
Figure 1. Chest radiograph showing bilateral infiltrates in an HIV patient with PJP
Source: Jeffrey J. Post, University of NSW, Sydney NSW. Used with permission:
Figure 2. CT scan showing ground glass appearance suggestive of Pneumocystis jirovecii pneumonia
Source: Jeffrey J. Post, University of NSW, Sydney NSW. Used with permission
The diagnosis of P. jiroveci infection may be made by immunofluorescence (IF) staining of the sample using monoclonal antibodies,60which typically takes two hours to process. Other stains, including silver stains, have a lower sensitivity but may be the primary means of diagnosis in some laboratories. Investigation of induced sputum is not warranted in asymptomatic immunodeficient people.61 One older meta-analysis suggested that induced sputum with immunostaining is the preferred diagnostic approach.62-68 A more recent meta-analysis which included studies with HIV and non-HIV associated PJP identified a sensitivity of 98.3% and a specificity of 91% for PCR testing of BAL fluid specimens.69
Despite the availability of direct and indirect identification methods, the diagnosis of PJ may be difficult. Some authors use the cycle threshold (CT ) values obtained by quantitative PCR (qPCR) to estimate the fungal burden: the higher that the fungal burden, the lower the CT value. Testing of BAL fluid samples from HIV-positive patients demonstrated that a CT value below 27 excluded colonization and a CT value above 30 excluded PCP with a specificity of 100% and a sensitivity of 80%, respectively.70
In people with a high clinical likelihood of PJP, presumptive therapy is sometimes undertaken if the induced-sputum specimen is not diagnostic and other features are consistent with PJP, but bronchoscopy with BAL is generally indicated, as the differential diagnosis is broad.71 Bronchoscopy with BAL is also indicated in cases of presumptive PJP that do not respond to therapy. Bronchoscopy may be preferred where there is a high likelihood of other infectious agents such as M. tuberculosis.72 Open-lung biopsy is usually unnecessary as induced-sputum examination and bronchoscopy with bronchoalveolar lavage have a high sensitivity (approximately 97%). The pathology of PJP consists of an eosinophilic alveolar exudate with Pneuocystis organisms present.73 Blood gas analysis should be undertaken to assess disease severity. Arterial blood hypoxaemia (while breathing room air), with a PaO2 < 70 mmHg, an alveolar-arterial (A-a) oxygen gradient of > 30 mmHg or oxygen saturation of < 94% indicates moderately severe or severe disease. Lesser impairment of gas exchange indicates mild disease. Therapeutic studies of mild-to-moderate disease have included those with a PaO2 > 50 mmHg.
Bronchoscopy and CT scan are now the key investigations following clinical suspicion or suspect CXR. Other investigations infrequently used in the diagnosis of PJP (these are now mainly of historical interest), include the following:
- Rapid clearance of technetium in lung scans indicates altered alveolar permeability that is consistent with PJP74, 75
- Pulmonary diffusing capacity for carbon monoxide is also typically impaired in persons with PJP76, 77
- Although serum lactate dehydrogenase level is often elevated in PJP, it is insufficiently specific to exclude other pathology or determine disease severity78
- More recently, there had been significant interest in serum markers of PJP, with low S-adenosylmethionine levels (a molecule that jiroveciimust scavenge) seen in cases with PJP that recover in association with effective treatment79, 80
- Other non-invasive markers such as serum beta-D-glucan were of interest and have a reasonable sensitivity and specificity.81, 82
The management of PJP depends on the degree of disease severity.
People with severe disease should be managed in hospital, as ventilatory support may be required. Those who are not allergic to sulpha-containing drugs or hypersensitive to cotrimoxazole should receive high-dose intravenous cotrimoxazole (for adults trimethoprim + sulphamethoxazole 5+25 mg/kg intravenously every 6-8 hours) and should receive therapy for a total of 21 days (once improvement has occurred a switch to oral therapy may occur). People who are allergic to sulpha compounds, or unresponsive to cotrimoxazole, or who develop hypersensitivity during therapy should be treated with intravenous pentamidine (3-4 mg/kg/day for 21 days)83, or clindamycin (900 mg intravenously every 8 hours) with primaquine (30 mg orally daily; after assessing risk of glucose-6-phosphate dehydrogenase deficiency).84 Supplemental oxygen, non-invasive ventilation (e.g. continuous positive airways pressure or bilevel positive airways pressure),85 or intubation and ventilation may be required. It is not uncommon for patients to deteriorate during the first 48 hours after commencement of therapy. Patients with significant hypoxaemia (PaO2 < 70 mmHg) should receive corticosteroids prior to the commencement of antimicrobial therapy to reduce the risk of this complication and improve prognosis (prednisone 40 mg orally twice a day for 5 days, then 40 mg daily for 5 days, then 20 mg/day until completion of treatment).86-90 If oral corticosteroid therapy is not possible then hydrocortisone (100 mg intravenously every 6 hours) may be used. Corticosteroid therapy may be complicated by central nervous system toxicity (e.g. psychosis, mania), oral candidiasis and other opportunistic infections. Patients who respond well to initial intravenous therapy may complete the 21-day course with oral therapy (see below).
If disease severity is moderate (i.e. dyspnoea on minimal exertion, PaO2 50-70 mmHg) or adherence to, or tolerance of, an oral regimen is not likely, then initial inpatient management is recommended. Otherwise, oral regimens may be considered (see below). Patients with moderately severe PJP should also receive corticosteroids if PaO2 < 70 mmHg.
People with mild disease may be treated with oral cotrimoxazole, two double-strength tablets three times daily (one double-strength tablet contains trimethoprim 160 mg and sulphamethoxazole 800 mg) for 21 days. Oral therapy should only be considered where adherence is likely. Adjunctive antiemetic therapy is commonly prescribed. Alternative regimens in cases of non-severe disease include clindamycin (450 mg orally four times daily) with primaquine (15 mg orally daily; after assessing risk of glucose-6-phosphate dehydrogenase deficiency); dapsone (100 mg orally daily) with trimethoprim (300 mg orally every 8 hours; 15 mg/kg/day),91 or atovaquone (750 mg orally twice daily).92
Salvage therapy for PJP with caspofungin has been reported in the non-HIV setting although the role of this agent in the initial treatment of PJP has not been studied and there are case reports of failure of this agent in the HIV setting in people thought to have multiple infective pathologies.93., 94 Further data are needed before caspofungin can be recommended.
The most common toxicity of cotrimoxazole is a hypersensitivity reaction. This typically manifests as a maculopapular rash with recrudescence of fever after initial resolution of fever due to PJP. There may be associated haematological and liver function test abnormalities. The hypersensitivity reaction may progress to a life-threatening systemic reaction if the drug is not ceased. Secondary PJP prophylaxis with cotrimoxazole following a hypersensitivity reaction may be considered if cotrimoxazole desensitisation is successful. PJP therapy should be completed and the hypersensitivity reaction fully resolved before cotrimoxazole desensitisation is undertaken.95, 96, 97 A rapid oral desensitisation protocol can be found in the most recent version of the Australian Therapeutic Guidelines: Antibiotics.98 If immune reconstitution is unlikely to occur with cART, or is likely to be delayed (e.g. very low nadir CD4+ T cell count or adherence to cART is unlikely), then desensitisation should be undertaken, as PJP prophylaxis will be needed for this period.
Early in the HIV epidemic, patients with PJP had a poor prognosis. With better management of respiratory failure and the introduction of cART, prognosis has improved, with recent data suggesting a 10% mortality rate overall.99 The prognosis of people with severe PJP requiring ventilation has improved, with one study reporting a 47% overall survival rate.100 Factors associated with a poor prognosis include the degree of hypoxaemia, neutrophilia, high numbers of organisms in BAL fluid and severe radiological abnormalities. Mutations in the dihydropteroate synthase gene of P. jiroveci, which confers resistance against sulpha drugs, have been suggested to worsen the prognosis.101, 102
Prophylactic Pneumocystis therapy
Prophylaxis against PJP is recommended in patients with a CD4+ T cell count < 200/μL or
CD4+ T cell proportion < 14% of lymphocytes, or oral candidiasis or unexplained fever of more than 2 weeks duration. The institution of prophylaxis (without cART) reduces the risk of PJP in susceptible populations by nine-fold.103 Mutations in dihydrofolate reductase may be associated with failure of prophylaxis.104
The optimal regimen is cotrimoxazole: one double-strength tablet orally once per day, although half a tablet daily is efficacious and may have a lower rate of toxicity. The risk of acquiring PJP while taking cotrimoxazole prophylaxis is extremely low. Cotrimoxazole is also active against toxoplasmosis and some bacterial pathogens. The most common toxicity is a cotrimoxazole hypersensitivity reaction (see above). Alternative regimens include double-strength cotrimoxazole (orally twice daily on 2 or 3 days per week), nebulised pentamidine (300 mg once per month, with salbutamol retreatment to reduce bronchospasm), dapsone (100 mg orally daily) or atovaquone (750 mg orally twice daily).105, 106 Hypersensitivity reactions may develop with several drugs used for prophylaxis (Table 5).
Table 5. Common toxicities of agents used in treatment or prophylaxis of Pneumocystisre jiroveci pneumonia
Hypersensitivity, Gastrointestinal, Biochemical hepatitis
Hypersensitivity, Diarrhoea, Pseudomembranous colitis, Haematological
Hypersensitivity – typically fever and maculopapular rash; dose related; may develop into Stevens-Johnson syndrome Nausea, vomiting Bone marrow toxicity – neutropenia, thrombocytopenia Biochemical hepatitis
Hypersensitivity Haemolysis in G6PDH-deficient people
Renal tubule dysfunction – renal impairment, hyperkalaemia Pancreatic toxicity – hypoglycaemia, hyperglycaemia, Arrhythmias Hypotension
G6PDH = glucose 6-phosphate dehydrogenase
Secondary prophylaxis after an episode of PJP is recommended to prevent relapse or recurrence until immune reconstitution has occurred.
Cohort studies have demonstrated the safety of discontinuing both primary and secondary PJP prophylaxis after the CD4+ T cell count has risen above 200/μL or the proportion of CD4+ T cells is > 14% of total lymphocytes for longer than 3 months, in the setting of HIV suppression with cART.107-112 More recent data suggest that the risk of PJP is as low with even earlier discontinuation of prophylaxis when the CD4+ T cell count is > 100 /μL, in the setting of suppressed HIV replication.113-115
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 elsewhere. Three infections not covered elsewhere in this monograph are covered here.
Penicilliosis (or talaromycosis)
Penicilliosis (or talaromycosis) is a systemic mycotic infection, caused by Penicillium marnefei (now called Talaromyces marneffei), a dimorphic fungus endemic in South-East Asia, Hong Kong and parts of southern China. Talaromyces marneffei was first isolated from a species of bamboo rat; however, the environmental source of infection remains unclear.116 Infection is thought to occur by the respiratory route. An increased risk is seen with recent occupational exposure to soil.116 Symptomatic infection occurs only rarely in the immunocompetent host. Clinical presentation may occur many years after exposure.117 The rapid explosion of HIV infection in the areas endemic for this fungus has led to a significant increase in cases of Talaromyces marneffei infection with more than 1000 cases reported in a 7-year period at one hospital in Thailand.118 Increased incidence occurs during the wet season (May to October).
Talaromyces marneffei infection is usually reported in late-stage HIV disease when the CD4+ cell count is < 100/μL.116, 118 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 3).
Figure 3. Talaromyces marneffei infection
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 (talaromycosis) 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).116 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 is said not to occur with Talaromyces marneffei infection.116 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.119
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%).116 Full identification of the organism may take up to 7 days. Galactomannan (GM) is a heteropolysaccharide in the cell walls of most Aspergillus and Talaromyces species. The use of the GM antigen assay may facilitate earlier diagnosis of Talaromyces marneffei infection for patients with HIV infection in areas of endemicity, as 73% of patients have positive tests, particularly those with fungaemia.120 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 (talaromycosis) 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%.121 Maintenance therapy with itraconazole (200 mg daily) had been recommended to be continued lifelong.118 Relapse occurs infrequently in the presence of maintenance therapy, although it is more likely in patients who remain in endemic areas.116 However, there have been more recent reports of successful discontinuation of maintenance therapy in patients who have achieved immune reconstitution with antiretroviral therapy (CD4+ T cell count > 100/μL for 6 months).122, 123 In patients with HIV infection and a CD4+ T cell count < 200/μL who live in an endemic area, primary prophylaxis with itraconazole at a dose of 200 mg per day is recommended. 124
Originally considered fungi, Nocardia spp. are a group of ubiquitous actinomycetes. Nocardia taxonomy is complex and, of the nine species described, only seven have been associated with human disease, with N. asteroides the most commonly identified, though this may change with the use of MALDI and other modern microbiological techniques.125 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.126 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.127 Pulmonary and disseminated disease occur almost exclusively in association with defects in cell-mediated immunity, immunoglobulin production or leukocyte function.128 Prevalence in people with HIV infection is low, varying from 0.3-1.8%,129, 130 although one West African autopsy study showed 4% of patients with pulmonary nocardial infection.131 Infection in people with HIV infection is strongly associated with injecting drug use127, 130 and advanced immunodeficiency (CD4+ T cell count <200 /μL).132
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.133 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.134 Acute cutaneous infection may manifest as a superficial skin infection with pustules, abscesses, cellulitis, granulomas and ulcers (Figure 4).134
Figure 4. Localised nocardial infection
Source: Allworth AL, Bowden FJ. Managing HIV. Part 5: Treating secondary outcomes. 5.16 HIV and bacterial infections. Med J Aust 1996; 164:546-8.
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.135 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,136 and pneumonia-associated empyema.137 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.135 Brain abscesses, usually supratentorial, are the most common CNS presentation; meningitis is rarely reported.138 Clinically silent CNS involvement is sufficiently common that cerebral-imaging studies are recommended, preferably magnetic resonance imaging (MRI), in all patients.138
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.139 Thirty per cent of patients with Nocardia spp. infection detected in blood cultures also have concomitant bacteraemia with other pathogens.137 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.140 Sulfonamides are the best studied drugs,141 with trimethoprim-sulphamethoxazole (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.126 Other useful drugs in the management of nocardial infection include imipenem, meropenem, cefotaxime, ceftriaxone, amikacin, and amoxicillin/clavulanic acid.139, 142, 143 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.140, 144 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 or complex identification is critical to guiding the selection of therapeutic agents.126
Although it is often stated that cotrimoxazole reduces the risk of nocardiosis in people with HIV infection, there is no compelling clinical evidence to support this claim, especially at the doses used for PJP prophylaxis.127, 129, 130 Indeed, there are numerous case reports of patients who develop nocardiosis despite receiving cotrimoxazole prophylaxis.
The mortality rate in pulmonary disease and extrapulmonary dissemination is high, with rates of 60% to 85% reported.130, 139
Rhodococcus equi infection
Rhodococcus equi (formerly Corynebacterium equi) is an aerobic, gram-positive, weakly acid-fast, non-spore forming coccobacillus. R. equi was first isolated from horses and has been wily 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.140, 141, 142 R. equi is usually acquired through the respiratory route in both animals and humans, although person-to-person and nosocomial transmissions have been described.140, 143
- equi infection in people with HIV infection presents with pulmonary involvement, usually accompanied by bacteraemia and frequent dissemination to extrapulmonary sites.143, 144It usually presents subacutely with fever and cough. Weight loss, pleuritic chest pain and haemoptysis are also frequently reported.145 150 151152R. equi infection in people with HIV infection usually occurs at CD4+ T cell counts < 200/μL, and concomitant infections with other opportunistic pathogens occur frequently.145 147 151 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. 145 Both the clinical picture and X-ray findings may suggest infection with Mycobacterium tuberculosis or Nocardia spp.147 152 Histological examination demonstrates multiple microabscesses with dense infiltration by histiocytes and intracellular gram-positive coccobacilli.149
- equi can be cultured from blood, sputum, BAL fluid and biopsy material using standard media.153R. equi resembles oropharyngeal commensal diphtheroids and is frequently regarded as a contaminant, leading to late diagnosis in many cases.150 151 152
The optimal choice and duration of antibiotic therapy for R. equi infection remains to be determined.150 154 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 has been recommended in the past.146 151 Mortality in patients with HIV and R. equi infections is historically high, often with death resulting from other concomitant infections.146