The degree of immunodeficiency, as indicated by the blood CD4+ T cell count, provides a guide to the differential diagnosis of respiratory tract disease in HIV patients (Table 1).

Table 1. Pathogens causing respiratory tract disease in patients with HIV infection at different CD4+ T cell counts

Adapted from Hanson et al, 1995, Salami AK, 2006

1. Other risk factors, such as intravenous drug use and corticosteroid therapy, may increase susceptibility to infection at higher CD4+ T cell counts.

MAC – Mycobacterium avium complex; CMV – cytomegalovirus; HSV – herpes simplex virus

People with significant immunodeficiency (ie. CD4+ T cell count < 200/μL or < 14% of total lymphocyte count) are at increased risk of opportunistic infections, including Pneumocystis jiroveci pneumonia (PJP) (previously Pneumocystis carinii pneumonia [PCP])³. Bacterial pneumonia can occur at any CD4+ T cell count but occurs more frequently in immunodeficient people than in those with a preserved CD4+ T cell count, often in association with bacteraemia. Non-Hodgkin lymphoma and tuberculosis (TB) can occur at any level of immunodeficiency, although TB is more likely to involve extrapulmonary sites in immunodeficient patients. More severe immunodeficiency (CD4+ T cell count < 100/μL) is associated with an increased risk of Toxoplasma gondii pneumonitis and cryptococcal pulmonary pathology. At this level of immunodeficiency, staphylococcal and gram-negative bacterial pneumonia occur more frequently than in people with CD4+ T cell counts > 100/μL. Infections with Streptococcus pneumoniae and Haemophilus spp. also occur. In the profoundly immunodeficient person (CD4+ T cell count < 50/μL) both cytomegalovirus (CMV) and Mycobacterium avium complex may be associated with pneumonitis, usually in the context of disseminated disease. It is important to remember that all opportunistic infections may rarely occur at higher CD4+ T cell counts, especially in the setting of asplenia or antiretroviral therapy. In a follow-up study of the SMART study, risk of opportunistic infections or cancer, including pulmonary diseases, and death was associated with uncontrolled HIV replication even at higher CD4⁺ T cell counts.⁴ The use of multiplex PCR on respiratory tract secretions has shown the important role of viruses in acute febrile respiratory illness in patients with HIV infection, especially with higher CD4+ T cell counts and on cART, a finding which may lead to the more judicious use of antibiotics.⁵ However, co-pathogens such as Pneumocystis jirovecii were found on bronchoalveolar lavage (BAL) fluid analysis in patients at lower CD4+ T cell counts, making it difficult to determine the contribution of respiratory viruses.⁶

Clinical history

Symptoms

Certain features in the patient’s history may be suggestive of one disease process over another. Typically, PJP is a subacute illness of fatigue, fever and dry cough of several weeks duration. In comparison, symptoms of short duration (hours to days), including chest pain, abrupt onset of fever and rigors and a productive cough are more consistent with bacterial (e.g. pneumococcal) pneumonia. Dyspnoea may occur in a range of infective pathological processes but may also be the only symptom of non-infective conditions, such as cardiomyopathy, ischaemic heart disease or pulmonary hypertension.

Prophylactic therapies

Immunodeficient patients who are taking prophylaxis for Pneumocystis infection are nine times less likely to develop PJP than those not taking prophylaxis⁷.^. Prophylactic treatment with cotrimoxazole (sulphamethoxazole/trimethoprim) is likely to reduce the incidence of bacterial infections as well as PJP and reactivation of T. gondii infection. In low income countries with a high prevalence of malaria and severe bacterial infection, cotrimoxazole prophylaxis reduces anaemia and improves growth in children with HIV infection.⁸ Second line prophylaxis for PJP with dapsone or inhaled pentamidine is associated with a small risk of treatment failure for PJP.⁹ Atovaquone is non-inferior to dapsone for secondary prophylaxis and has fewer side effects.¹⁰ Prophylaxis for MAC with macrolide antibiotics may also decrease the incidence of pneumonia.¹¹ Persons with a positive tuberculin skin test (TST; > 5 mm) who have not received treatment for latent TB have a 14% risk of developing active TB over a 2-year period and should therefore be considered for isoniazid prophylaxis.¹² The data on gamma interferon release assays, such as Quantiferon Gold or ELISPOT testing, in the setting of HIV are more limited, but it is likely a positive test has the same significance. It is uncertain if there is a clinical benefit of isoniazid treatment for latent TB infection when defined by a positive gamma interferon release assay if the TST is < 5 mm (see section on Mycobacterium tuberculosis). Annual influenza vaccination is recommended as patients with HIV may be more likely to contract influenza and experience severe disease requiring hospitalisation.¹³

Epidemiological risk factors

 People who have resided in or travelled to countries with a high prevalence of TB are at increased risk for TB. A contact or occupational history may also be useful in suggesting the possibility of TB. A past history of incomplete treatment of TB may suggest drug-resistant TB. Travel to areas endemic for the dimorphic fungi may be important: Histoplasma capsulatum is endemic in areas of the USA (especially the Mississippi and Ohio River valleys), Latin America, West Indies, Eastern India, and Africa. Coccidioides immitis is hyperendemic in some parts of the southwest of the USA, Northern Mexico, and in Central and South America. Other illnesses with respiratory symptoms where a travel history might be important include melioidosis, Talaromyces marneffei infection (formerly Penicillium marneffei casing penicilliosis), strongyloidiasis and Salmonella infection. Persons with HIV infection who inject drugs are more likely to develop bacterial pneumonia^{4, 14} and invasive bacterial infection such as endocarditis, caused by organisms such as Staphylococcus aureus. Smoking is an important risk factor for bacterial pneumonia as well as bronchitis, chronic airflow limitation and carcinoma of the lung in people with HIV infection, as in the general population. Marijuana smoking has been associated with Aspergillus infection.¹⁵  Men who have sex with men are more likely to develop Kaposi sarcoma (KS), in proportion to their risk of HHV8 carriage, although isolated pulmonary disease without mucocutaneous lesions is uncommon.¹⁶ Antiretroviral treatment itself may be a cause of respiratory symptoms, e.g. dyspnoea caused by nucleoside analogue-induced lactic acidosis, hypersensitivity reaction to abacavir (now largely eliminated by HLAB57*01 testing).

 Physical examination

The physical examination may be normal in HIV patients with PJP, aside from tachypnoea and a dry cough, although fine crackles may be present. Signs of consolidation suggest bacterial, mycobacterial or fungal disease. Examination for extrapulmonary features should be undertaken, as disseminated disease processes may present with pulmonary symptoms. Cardiovascular signs should be assessed as pulmonary hypertension, endocarditis, cardiomyopathy and pericardial effusions may also cause breathlessness. Signs associated with immunodeficiency should be elicited (e.g. oral candidiasis) as these may influence the differential diagnosis in the absence of a current CD4+ T cell count. The skin should be examined for the presence of KS and the cutaneous lesions of cryptococcosis. The presence of neurological signs may suggest disseminated toxoplasmosis, and drowsiness may occur in cryptococcosis. Hepatosplenomegaly may be present in people with Mycobacterium avium complex infection, non-Hodgkin lymphoma or CMV infection.

Investigations

Blood tests

Most standard biochemical and haematological tests are not helpful in the diagnosis of respiratory symptoms in advanced HIV disease. However, peripheral blood neutrophilia and left shift may occur in bacterial pneumonia and cryptococcal disease. Neutropenia may suggest an increased likelihood of bacterial or fungal infection. Measurement of the degree of impairment of gas exchange with arterial blood gas analysis is important, as the degree of hypoxaemia may change the management of certain diseases (e.g. steroid therapy in PJP). In cases of suspected cryptococcal disease, the titre of serum cryptococcal antigen is used as evidence of disseminated disease. Bacterial blood cultures should be obtained as well as mycobacterial blood cultures in immunodeficient patients, given the elevated rates of bacteraemia.

Chest radiograph

The chest radiograph may reveal the presence of focal consolidation suggestive of bacterial, tuberculous or cryptococcal disease or lymphoma typical radiological pattern of TB, with upper lobe disease and cavitation, may not be seen in immunodeficient people. Pleural effusions may be caused by KS or the range of diseases which also cause consolidation. The presence of a pleural effusion makes the likelihood of PJP quite low, although in advanced HIV disease, multiple disease processes may co-exist. The presence of a pneumothorax makes PJP more likely, although other disease processes may rarely cause a bronchopleural fistula and be associated with a pneumothorax. Cavitating disease is likely to be caused by TB or infections by bacteria, fungi, Nocardia spp., and some non-tuberculous mycobacteria. Diffuse infiltrates with a reticular or granular pattern are suggestive of PJP, but many other diseases may have a similar radiographic pattern. A normal chest radiograph does not exclude PJP.or cryptococcosis where extrapulmonary disease is the major manifestation^[6] (see Table 2 and Table 3).

Other investigations

Other investigations for a suspected respiratory tract infection in HIV patients are shown in Table 3. Sputum from all patients presenting with a productive cough should be sent for microscopy and culture. Sputum investigations should routinely include Gram stain, bacterial and fungal culture and sensitivity testing. Although not all specimens need to be examined for mycobacteria, a low threshold for testing sputa for acid-fast bacilli and mycobacterial culture should be maintained. An induced sputum should be collected where the clinical likelihood of PJP is high, provided adequate negative-pressure facilities exist. The sample is assessed for the presence of P. jirovecii by immunofluorescence, Giemsa or silver stains and a result is usually available within 2 hours. Quantitative real time PCR testing for Pneumocystis has a negative predictive value of nearly 100%.  Supplemental investigations such as bronchoscopy increase the diagnostic yield for P. jirovecii infection and may facilitate other diagnoses as well. P. jirovecii cysts or DNA may still be detected in bronchoalveolar lavage fluid after several days of therapy with cotrimoxazole. A high-resolution CT scan that does not reveal ‘ground glass’ changes makes the diagnosis of PJP unlikely.¹⁷  The absence of these findings suggests that alternative pathology to PJP should be considered. Where a pleural effusion has been detected, a diagnostic pleurocentesis is warranted. Pulmonary nodules should be biopsied if sputum sampling, bronchoscopy and less invasive investigations are negative (e.g. serum cryptococcal antigen or bone marrow biopsy in the setting of pancytopenia).