Opportunistic lung infections

Learning objectives
• Define opportunistic lung infections
• Understand the pathological basis of the infections
• Classify the different types of opportunistic infections
• Identify and manage common OIs
Outline
• Introduction
• Epidemiology
• Pathogenesis
• Differential diagnosis
• Treatment
Introduction
• Definition
• Any infection or diseases of such severity occurring in an individual as
a result of a compromised immune function.
• The risk of infection in any patient is determined by the interaction of
two factors:
• Epidemiologic exposure
• Net state of immunosuppression
Epidemiology
• 38.0 million [31.1 million–43.9 million] people globally were living with
HIV in 2019 (2/3 in SSA).
• 1.7 million [1.4 million–2.4 million] people became newly infected with
HIV in 2019 (95% in LMIC).
• 670,000 [670 000–1.3 million] people died from AIDS-related illnesses
in 2019
• 35.4 million [25.0 million–49.9 million] people have died from AIDS-
related illnesses since the start of the epidemic.
• TB remains the leading cause of death among people living with
HIV, accounting for around one in three AIDS-related deaths.
Pathogenesis
• HIV infection can alter host defense by directly infecting pulmonary
cells.
• Various strains of HIV demonstrate cellular tropism, based on the
phenotype and receptor/co-receptors required for entry of the virus
into host cells.
• The primary receptor for HIV is the CD4 receptor, found in humans on
the surface of monocytes/macrophages, dendritic cells and
lymphocytes.
Pathogenesis

•Muco-ciliary clearance (MCC)

• MCC is a primary innate defense mechanism of mammalian airways that protects the host from the
noxious effects of airborne pathogens, pollutants and allergens.
• The MCC apparatus consists of the cilia, a protective mucus layer, and a periciliary Airway surface
liquid (ASL) layer to optimize ciliary beating.
• Abnormalities in any compartment of the mucociliary system can compromise mucus clearance
leading to mucus impaction and consequently, chronic bacterial infection.
• The height of the ASL layer lining the airway surfaces is crucial for mediating MCC rates and is tightly
regulated by CFTR.
• CFTR dysfunction can have a pronounced effect on ASL depth as well as ciliary beating and can
contribute directly to microbial colonization.
MCC
• Effective MCC requires the combined action of ASL depth maintenance and ciliary beating.
• HIV infection causes a suppression of CFTR as well as ciliogenesis.
Ig A
• HIV infection not only destroys CD4+ T cells but also inflicts serious damage to the B-cell
compartment.
• Subepithelial B cells and plasma cells are also affected, which results in loss of mucosal IgG and IgA
antibodies.
• This leaves the mucosal barrier vulnerable to bacterial translocation.
Alveolar macrophages
• HIV-1 infection is characterized by sustained activation of the immune system.
• HIV can infect several types of immune cells, though macrophages and CD4 T cells are the
principal targets of the virus.
• The primary reservoir for HIV in the lung is thought to be macrophages.
• Alveolar macrophages (AM) represent 95% of the cells in bronchoalveolar lavage (BAL) fluid.
• Infection with HIV alters the function of alveolar macrophages.
• HIV-infected macrophages release a variety of proinflammatory cytokines & chemokines
that induce T cell proliferation and viral replication.
• AMs also require a host of activating cytokines, like IFN α, to maximize their ability to detect
and clear pathogens such as Pneumocystis jirovecii.
• HIV infection depletes important immune effector cells and therefore diminishes a major
source of cytokines that activate AMs in host defence.
Neutrophils
• Polymononuclear leukocytes (PMNs) are important in host defense during the early
innate response against bacterial and fungal infections.
• During an infection, PMNs migrate from the blood to inflamed tissues and trigger the
production of reactive oxygen species (ROS) as part of the oxidative burst.
• HIV does not directly infect PMNs but leads to impaired PMN responses, such as
phagocytosis, oxidative burst, and bacterial killing.
• Once PMNs kill a microbe, they die spontaneously through apoptosis. Inappropriate
survival of PMNs in HIV infection is thought to cause a chronic inflammatory state
with ongoing release of inflammatory mediators.
• In patients with HIV infection, neutrophil functions, such as chemotaxis, respiratory
burst activity, bacterial killing and antibody-dependent cell-mediated cytotoxicity, are
impaired.
Adaptive immunity
• HIV weakens cell mediated immunity by destroying CD4+ T cells and impairing the production of
new T cells. HIV-1 infection is further characterized by immune cell dysfunctions driven by chronic
immune activation.
• HIV-1 is associated with a progressive loss of T cell functional capacity including decreased
responsiveness to antigenic stimuli, lowered capacity to produce cytokines, and reduced proliferative
and cytotoxic activity.
• Loss of CD4+ T cells and functional impairment of CD8+ T cells eventually results in a failure of host
immune system to maintain control of HIV-1 leading to an accelerated disease progression.
• HIV-1 specific T cells from rapidly progressing patients exert decreased cytotoxic and proliferative
activity and produce reduced levels of TNFá, IL-2, IFNã, and CD107 compared to T cells from non-
progressors.
• Infection of individuals with HIV leads to progressive loss of immune functions and defects in
humoral immune responses are clearly present.
Bacteria pneumonia
• Currently, bacterial pneumonia is the most frequent infection in HIV-infected patients, as well as the
most common admission diagnosis.
• HIV infection is associated with a 10-fold increased incidence of bacterial pneumonia.
• Bacterial pneumonia can occur throughout the entire course of HIV infection
• Risk factors include;
• Intravenous drugs
• Cigarette smoking
• Older age,
• High viral load
• Low CD4+ cell count
• Previous recurrent pneumonia
Bacteria pneumonia
• Streptococcus pneumoniae is the most common bacterial cause of community-acquired pneumonia
among adult PLHIV, implicated in 20% of all bacterial pneumonias
• Haemophilus influenzae accounts for 10–15% of cases of bacterial pneumonia with aetiological
diagnosis.
• Staphylococcus aureus is the third most frequent cause of bacterial pneumonia. Injection drug users
can develop right-sided tricuspid valvular S. aureus endocarditis with septic pulmonary emboli.
• Pseudomonas aeruginosa is an infrequent cause of community acquired pneumonia.
Bacteria pneumonia
• The clinical presentation of bacterial pneumonia in HIV seropositive patients is usually similar to that
of patients not infected with HIV.
• Bacteraemia is frequently associated with bacterial pneumonia.
• The most common chest X-ray finding is unilateral segmental or lobar consolidation, although diffuse
reticulonodular infiltrates and patchy lobar infiltrates may also be identified.
• A subset of persons with H. influenzae pneumonia present with bilateral infiltrates that are
indistinguishable from PCP.
• However, pneumonia due to P. aeruginosa or S. aureus is often associated with cavitation.
• The initial antibiotic treatment regimen will be directed at the most common pathogens.
• Treatment is similar to that of patients with the same diagnosis without HIV infection.
Pneumocystis pneumonia

• PCP is caused by P. jirovecii, a ubiquitous organism that is classified as a fungus but that also shares
biological characteristics with protozoa.
• Early studies in the USA showed PCP as the most frequent cause of pulmonary infections
(accounting for 85% of cases).
• The rate of PCP greatly decreased as a result of primary P. jirovecii prophylaxis.
• Despite this decrease, PCP remains the most common AIDS-defining indicator condition and the
most frequent opportunistic infection in North America and Europe.
• PCP mainly develops in patients whose CD4 cell count is <200 cells/mL. The median CD4 count is 20
cells per mm3, and the plasma viral load of HIV is usually >10,000 copies/mL.
Pneumocystis pneumonia
• HIV-infected persons with PCP generally have a more sub-acute course and longer duration of
symptoms than other immunocompromised patients.
• The clinical presentation consists of fever, gradually increasing non-productive cough and dyspnoea
for a few weeks, bilateral interstitial infiltrates and hypoxia.
• The most common findings on physical examination are fever, tachypnoea and inspiratory crackles.
• Physical examination of the chest is unremarkable in ~ 50%.
Pneumocystis pneumonia
• Chest radiographs are initially normal in up to a quarter of
patients with PCP.
• The chest radiograph typically demonstrates perihilar infiltrates in
mild disease and bilateral, symmetrical interstitial infiltrates
emanating from the hila in a butterfly pattern in severe disease.
• Less frequently, PCP may present with unilateral or asymmetrical
opacities.
• Thin-walled cysts or pneumatoceles are seen in 10–20% of cases.
• Pneumothorax can occur.
Pneumocystis pneumonia
• TMP-SMX remains the drug of choice for the treatment and prevention of this infection.
• The recommended duration of therapy for PCP is 21 days.
• Following the completion of therapy, patients should be immediately started on PCP prophylaxis.
• Corticosteroids given in conjunction with anti- Pneumocystis therapy decrease the mortality
associated with severe PCP.
Tuberculosis
• At least one-third of PLHIV worldwide are infected with Mycobacterium tuberculosis
• HIV infection is, in global terms, the largest risk factor for developing TB disease.
• TB is a leading cause of death for people living with HIV in low- and middle-income countries.
• HIV-infected persons have a substantially greater risk of progressing from latent TB infection to
active TB compared with persons without HIV infection.
• Africa is experiencing the worst TB epidemic since the advent of antibiotics, with rates increasing
sharply in the past two decades.
• TB can occur at any stage of HIV disease, but as the CD4 cell count declines, the incidence of TB
increases.
Tuberculosis
• Clinical manifestations largely depend on the level of immunosuppression.
• In persons whose CD4+ cell count is 350–400 cells per mm3, the clinical presentation is similar to
that in persons without HIV infection
• Persons whose CD4 cell count is <200 cells per mm3 often present with a primary TB pattern.
• Patients with advanced immunosuppression more often have extra-pulmonary and disseminated TB.
• Subclinical TB is increasingly recognized.
• There is a subpopulation of individuals with HIV with culture-positive pulmonary TB who are
completely asymptomatic.
Tuberculosis
• The most important diagnostic tests for TB are repeated expectorated sputum samples for smear and
culture.
• Culture on selective media remain the most sensitive method for detecting M. tuberculosis in clinical
specimens.
• Testing for susceptibility to first-line agents should be performed on all isolates.
• Nucleic acid amplification testing amplifies the quantity of M. tuberculosis DNA in diagnostic
specimens and is useful for rapid identification of the microorganism making it relevant as a first line
diagnostic test.
Tuberculosis
• The principles of TB treatment in PLHIV are the same as those in HIV-negative individuals.
• However, treatment of TB can be complicated by drug interactions and overlapping toxicities when
therapy for both HIV and TB is concomitantly administered.
• Rifamycins induce hepatic CYP3A4 enzymes that can accelerate metabolism of protease inhibitors
(PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) leading to sub-therapeutic levels
of these antiretroviral drugs.
• Early HAART (initiated during the first 2 weeks) reduced the HIV disease progression and death
among HAART-naive PLHIV with TB and a CD4+ cell count of <50 cells per mm3 .
• In patients with CD4+ T-cells >50 cells per mm3, HAART can be started within 8 weeks after the start
of TB treatment.
• WHO guidelines recommend that, irrespective of CD4+ cell counts, patients co-infected with HIV
and TB should be started on antiretroviral therapy as soon as TB therapy is tolerated.
Respiratory mycoses

• Histoplasmosis
• Progressive disseminated histoplasmosis (PDH) in PLHIV is either the result of reactivation of
previous infection or progression to disseminated disease shortly after the initial infection.
• The chest roentgenogram is normal in approximately a quarter of these patients, and findings
compatible with a recent pulmonary infection, indicating primary disease, are not present.
• The clinical presentation of PDH is similar to many other pulmonary and systemic infections
occurring in HIV-infected individuals.
• Fever and weight loss were the most common symptoms, occurring in 75% and 50% of patients,
respectively.
• Splenomegaly and lymphadenopathy occurred in 30% of patients, and hepatomegaly occurred in
26%.

•The chest roentgenogram demonstrated diffuse interstitial infiltrates in up to 70% of patients.

Histoplasmosis
• Diagnosis depends on the rapid identification of the fungus from
biologic material.
• The simplest and most readily available test is the examination of
the peripheral blood smear.
• The fungus is readily recovered from blood culture using the lysis
centrifugation technique.
• Examination of the bone marrow is also helpful- the organisms are
readily seen in periodic acid Schiff-stained specimens, and culture
is also frequently positive.
• Standard serologic tests are also frequently positive.
Histoplasmosis
• Treatment of PDH in PLHIV is difficult and a "cure" should not be expected.
• Relapse is common in the absence of continued antifungal therapy.
• Early series where continued antifungal suppression was not given showed rates of relapse of over
50%
• 200mg of itraconazole twice daily is a reasonable choice for primary therapy of mild to moderately
severe cases, effective in 85 % of such instances.
• In more severely ill patients, an initial course of 500 mg of Amphotericin B is likely to produce more
rapid stabilization of the patient, before switching to itraconazole.
Coccidiosis
• Fungal infection due to Coccidioides immitis.
• With clinically apparent coccidioidal infections in PLHIV, CD4 lymphocyte counts are typically below
250/mm3.
• It is common in endemic areas and may affect up to 25% of PLHIV in such areas.
• A chest radiograph revealing bilateral diffuse reticulonodular pulmonary infiltrates in association with
fever and dyspnea is a common presentation of coccidioidomycosis during HIV infection.
• Some patients may develop focal lesions beyond the chest, including skin, lymph nodes, liver, and
meninges.
• In still others, however, coccidioidal infection may produce nodules, patchy infiltrates, or cavities that
may be indistinguishable from those which normally occur in immunocompetent persons.
Coccidiosis
• Diagnosis requires either recovery of the fungus in culture or visualization of the organism in biologic material or in

histopathologic sections.

• Identification: Standard serologic tests should be obtained on all patients in whom coccidioidomycosis is suspected. The test

will frequently be positive in patients with active infection, and it is worthwhile to follow titers to monitor success of therapy.

• Therapy should be started on all PLHIV with active coccidioidomycosis, and some form of maintenance therapy should

continue for life.

• Patients with diffuse pulmonary infiltrates should be treated with Amphotericin B. Although therapy with oral triazoles such

as fluconazole or itraconazole may be efficacious.

Blastomycosis
• Blastomycosis is an uncommon disease complicating HIV infection.
• Similar to the pattern seen in other endemic mycoses, blastomycosis was a late complication of HIV
infection.
• The vast majority of patients had CD4 counts under 200/mm3
• Although the clinical presentation of the reported patients has been variable, the lungs were involved
in the majority.
• The radiographic pattern varied from segmental or lobar infiltrate to multiple nodules; widespread
miliary pattern was the most common finding on chest radiographs.
• Diagnosis requires either recovery of the fungus in culture or visualization of the organism in biologic
material or histopathologic sections.
• The most rapid test is visualization of the characteristic single budding yeast with doubly refractile
wall from respiratory secretions or other material after 10% potassium hydroxide (KOH) digestion.
Blastomycosis
• Primary treatment of the infection should be with Amphotericin B.
• Since many of the patients are critically ill and the frequency of CNS involvement is high, primary
therapy with azoles is suboptimal.
• Although the optimal dose of Amphotericin B is not established, a total dose of 1-2 g should be
adequate to bring the infection under control.
• After an induction course of Amphotericin B therapy, chronic maintenance therapy with itraconazole
is indicated.
Parasitic infections

• Toxoplasmosis gondii
• T. gondii is the most frequent parasitic pneumonia seen in persons with HIV infection.
• Although encephalitis is overwhelmingly the most common manifestation of T. gondii, pneumonitis
has become its second most common presentation.
• Active pulmonary toxoplasmosis does not usually occur until the CD4 count falls below 100/mm3.
• Pulmonary toxoplasmosis may be clinically indistinguishable from other opportunistic lung infections.
Toxoplasmosis gondii

• The chest radiograph usually reveals bilateral infiltrates, either fine

reticulonodular infiltrates indistinguishable from PCP or coarser
nodular pattern similar to that seen with TB or fungal pneumonias.
• Most cases of T. gondii disease are due to reactivation of latent
infection. Consequently, almost all persons with toxoplasmosis are
positive for serum Toxoplasma immunoglobulin G antibody. Its
absence makes the diagnosis of Toxoplasma pneumonia unlikely.
• The diagnosis of pulmonary toxoplasmosis is usually established by
bronchoscopy with BAL
Diagnosis & treatment
• The diagnosis of pulmonary toxoplasmosis is usually established by
bronchoscopy with BAL.
• Sulfadiazine plus pyrimethamine is the first-line recommended
treatment.
• Leucovorin is co-administered with pyrimethamine to reduce the occurrence
of hematologic toxicities from pyrimethamine.
• Clindamycin plus pyrimethamine (and leucovorin) and trimethoprim-
sulfamethoxazole are the main alternatives
Respiratory viruses
• Influenza virus
• Influenza is a common cause of respiratory illness in adults with HIV.
• Annual influenza vaccination for adults infected with HIV is recommended by the CDC and the IDSA.
• Cytomegalovirus (CMV)
• Retinitis and gastrointestinal disease are the most common manifestations, but pneumonitis is
infrequent.
• CMV as a sole cause of pneumonia is not common until the CD4 cell count is ≤50 cells per mm3.
• A particular problem is posed by the coexistence of CMV with other pathogens found in BAL fluid,
particularly P. jirovecii
Chest Radiograph
• The chest radiograph findings of CMV pneumonia vary and include
reticular or ground glass opacities, alveolar infiltrates, and nodules or
nodular opacities.
• Pleural effusions may be seen as well. The latter finding may be
helpful in distinguishing CMV pneumonia from PCP, where pleural
effusions are rare.
Diagnosis & treatment
• Diagnosis of CMV pneumonia requires the demonstration of
cytopathic inclusions and widespread specific cytopathic changes in
the lungs.
• Ganciclovir (intravenous) and foscarnet have been used to treat CMV
pneumonia.
 CD4 cell count
Any Bacterial pneumonia
(especially Streptococcus
pneumoniae and
Evaluation of HIV- Hemophilus species)
Tuberculosis (TB)
associated <200 cells/μL Pneumocystis pneumonia (PCP)
Opportunistic Cryptococcus
Pneumonias neoformans pneumonia
Bacterial pneumonia
accompanied by bacteremia or
septicemia
Extrapulmonary or disseminated
TB
<100 cells/μL Bacterial pneumonia due to Pseudomonas aeruginosa

Toxoplasma gondii pneumonia
<50 cells/μL Coccidioides immitis, usually accompanied by
disseminated disease
Histoplasma capsulatum, usually accompanied by
disseminated disease
Cytomegalovirus, usually accompanied by disseminated
disease
Mycobacterium avium complex, usually accompanied
by disseminated disease
Conclusion
• Opportunistic lung infections are causes of increased morbidity and
mortality among patients with HIV infection.
• Clinical presentation depends on the level of immune deficiency
• Diagnosis usually involves extensive and invasive procedures.
• Treatment may be prolonged.
•Thank you for your attention