Atypical bacterial pneumonia in the HIV-infected population
Head et al. Pneumonia
Atypical bacterial pneumonia in the HIV-infected population
Breanne M. Head 4
Adriana Trajtman 4
Zulma V. Rueda 3
Lázaro Vélez 2
Yoav Keynan 0 1 4
0 Department of Community Health Sciences, University of Manitoba , Winnipeg , Canada
1 Department of Internal Medicine, University of Manitoba , Winnipeg , Canada
2 Grupo Investigador de Problemas en Enfermedades Infecciosas, Universidad de Antioquia UdeA , Medellin , Colombia
3 Facultad de Medicina, Universidad Pontificia Bolivariana , Medellin , Colombia
4 Department of Medical Microbiology, University of Manitoba , Winnipeg , Canada
Human immunodeficiency virus (HIV)-infected individuals are more susceptible to respiratory tract infections by other infectious agents (viruses, bacteria, parasites, and fungi) as their disease progresses to acquired immunodeficiency syndrome. Despite effective antiretroviral therapy, bacterial pneumonia (the most frequently occurring HIV-associated pulmonary illness) remains a common cause of morbidity and mortality in the HIV-infected population. Over the last few decades, studies have looked at the role of atypical bacterial pneumonia (i.e. pneumonia that causes an atypical clinical presentation or responds differently to typical therapeutics) in association with HIV infection. Due to the lack of available diagnostic strategies, the lack of consideration, and the declining immunity of the patient, HIV co-infections with atypical bacteria are currently believed to be underreported. Thus, following an extensive database search, this review aimed to highlight the current knowledge and gaps regarding atypical bacterial pneumonia in HIV. The authors discuss the prevalence of Chlamydophila pneumoniae, Mycoplasma pneumoniae, Coxiella burnetii, Legionella species and others in the HIV-infected population as well as their clinical presentation, methods of detection, and treatment. Further studies looking at the role of these microbes in association with HIV are required. Increased knowledge of these atypical bacteria will lead to a more rapid diagnosis of these infections, resulting in an improved quality of life for the HIV-infected population.
Atypical; Bacteria; Pneumonia; HIV; Legionella; Chlamydophila; Mycoplasma; Coxiella; Tropheryma
Bacterial pneumonia, the most frequent human
immunodeficiency virus (HIV)-associated pulmonary illness, is a
common cause of co-morbidity and mortality in the HIV
population. Prior to the introduction of combination
antiretroviral therapy (cART), bacterial pneumonia
infection rates ranged from 3.9–20 cases per 100
person-years in HIV-positive individuals and were
predominantly due to opportunistic pathogens such as
Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus, as well as acute
Mycobacterium tuberculosis infections [
]. Although bacterial
pneumonia rates have decreased since the
introduction of cART, rates remain 10 times higher among
HIV-infected individuals than in healthy individuals
2, 4, 5, 9, 10
]. Additionally, HIV-associated
pneumonia remains the most common cause of hospital
admission with up to 90 cases per 1000 persons
occurring yearly [
Currently, the diagnosis of pneumonia is based on
clinical features and X-ray. The etiological diagnosis,
however, is based on empirical data, culture, serology,
nucleic acid amplification techniques (NAAT), and
]. When choosing any of these
diagnostics, a number of points must be considered.
Although very informative, empirical data (i.e. patient
history, recent travel, intravenous [IV] drug exposure,
prior infections, or antibiotic exposure) can only aid in
narrowing the scope of infection and is not definitive
. In contrast, culture allows bacterial identification
and is considered the preferred method in diagnostics.
However, incubation periods can be lengthy (depending
on the growth rate of the microorganism), not all
microbes are cultivable, and the sensitivity of the assay
decreases if the patient has had any pre-treatment with
]. Serological tests rely on the patient’s
ability to mount an effective antibody response; however,
in the case of HIV, this response is greatly reduced.
Therefore, depending on the stage of HIV infection,
serology may not be clinically useful [
]. Due to the
low sensitivities of serology, NAAT (such as polymerase
chain reaction [PCR]) is becoming the diagnostic tool of
choice for rapid identification of atypical bacteria in
respiratory samples of HIV-infected and uninfected
14, 17, 18
]. However, although NAAT is highly
specific, sensitivity has been shown to vary depending
on the patient sample being tested (e.g. nasopharyngeal
sample vs. induced sputum) [
]. Moreover, although
the presence of NAAT is becoming more prominent in
developed nations, it is still not readily available in
developing countries. In the event that a definitive
diagnosis cannot be reached, more invasive techniques (e.g.
bronchoscopy) may be used for sample collection
(bronchoalveolar lavage [BAL] or biopsy). Although very
beneficial, bronchoscopy is currently underutilized in
respect to HIV and advanced immunosuppression, despite
it being recommended for patients with low CD4 cell
counts (< 200 cells/μl). This underutilization is perhaps
due to the fact that patients are too sick to undergo the
BAL procedure, or due to the high volume of
immunosuppressed patients admitted to hospital [
5, 12, 21
addition, it can lead to complications such as bleeding
and pneumothorax [
Despite technological advancements, the etiology of
HIV-associated pneumonia is identified less than 60% of
the time, thus research looking into atypical
pneumoniacausing agents is required [
]. Limited information is
available regarding atypical bacterial pneumonia (i.e.
pneumonia that does not respond to beta-lactams, one
of the antibiotics typically prescribed to pneumonia
patients with co-morbidities), with even less information
about these infections in HIV . Due to the lack of
consideration, the role that atypical bacteria play in
disease severity and patient outcome in HIV-associated
pneumonia is unknown. Consequently, this review will
highlight the bacteria—namely Chlamydophila
pneumoniae, Mycoplasma pneumoniae, Coxiella burnetii,
Legionella species and others—that is responsible for
causing atypical bacterial pneumonia in HIV.
Specifically, the review explores the current knowledge
regarding the prevalence of these microbes in the HIV-infected
population, as well as their clinical presentation,
methods of detection, and treatment.
Chlamydophila pneumoniae, an obligate intracellular
pathogen that has caused pulmonary infections all over
the world, remains a particular problem in the
HIVinfected population [
]. Studies by Trinh et al. 
have demonstrated that C. pneumoniae pneumonia rates
are as high as 60% in cART-treated HIV-infected
children. Likewise, in the adult population, coinfections
with HIV have been reported to range from 3 to 39%
]. In general, HIV-associated C. pneumoniae
pneumonia rates have been shown to be inversely
proportional to the patient’s CD4 cell count, occurring at
6.8, 15.7, and 25.2% when CD4 counts are above 500,
between 200 and 500, and below 200 cells/μl,
respectively . In other words, the rates increase with
decreasing CD4, up to a quarter among individuals with
advanced HIV and CD4 < 200. In a retrospective analysis
] of 319 adult pneumonia-infected HIV seropositive
individuals, C. pneumoniae was cited as a co-pathogen
with other microorganisms in approximately 2.2%
(n = 7) of cases.
Much of the research on HIV-associated C.
pneumoniae pneumonia arises from the post-cART era with
little information on the effect of this microorganism in
untreated HIV. However, of those that have been
reported, it was found that the risk of acquiring C.
pneumoniae pneumonia was 5 times higher in untreated HIV
than in the general population [
30, 32, 33
]. Regardless of
these higher rates, the clinical course of disease is similar
among both populations. Disease manifests as an acute
respiratory infection (with focal pneumonia, pleural
effusion, or bronchitis), although, as the degree of
immunosuppression increases, more severe and diffuse
interstitial pulmonary involvement and death can occur
29, 32, 34, 35
]. Likewise, C. pneumonia infection has
also been shown to cause chronic infections (e.g.
arteriosclerosis or cardiovascular disease) .
Diagnosis of HIV-associated C. pneumoniae
pneumonia is reliant on serology and NAAT.
Microimmunofluorescence (MIF), a technique that indirectly measures
the C. pneumoniae-specific antibody response, requires
either single or convalescent serum samples to
differentiate between a recent/current infection and a previous
27, 30, 29, 34
]. However, severely
immunosuppressed HIV-infected adults (with CD4 counts <200
cells/μL) have been reported to be unable to mount an
effective IgG response . Conversely, HIV patients
may have an asymptomatic C. pneumoniae infection
while co-infected with another pneumonia-causing
pathogen, which poses another limitation on the utility
of this diagnostic test [
]. Consequently, NAAT
tests on respiratory specimens (BAL or nasophayngeal
swab) are recommended as they have shown promise for
C. pneumonia diagnosis in HIV [
18, 27, 37
]. In fact, the
United States Food and Drug Administration has
approved a BioFire FilmArray NAAT for the detection of
both C. pneumoniae and M. pneumoniae .
Mycoplasma pneumoniae, the most common
Mycoplasma respiratory pathogen, accounts for approximately
20% of all pneumonias in the United States (US) general
population, and 11.3–21.0% (depending on the method of
diagnosis) of all pneumonias in the US HIV-infected
population, with higher rates correlated with the degree of
]. Indeed, in a study by
Nadagir et al. , 18 of the 29 (62%) HIV-positive, M.
pneumoniae-infected children had a CD4 cell count of
<20 cells/μL. Additionally, a depleted CD4 associated with
advanced HIV disease has been shown to enhance M.
pneumoniae establishment in the lungs [
similarly to C. pneumoniae, the majority of the data on
HIV-associated M. pneumoniae lung infections is from
treated HIV patients, with minimal information on its
effect in untreated HIV.
Clinical manifestations of M. pneumoniae
pneumonia in HIV are similar to those seen in healthy
individuals. Cough (reported in 100% of cases),
anemia, arthralgia, dyspnea, and sore throat along
with fever, rales, interstitial infiltrates, and lobar
pneumonia are most commonly reported, making
diagnosis nearly impossible based solely on clinical
M. pneumoniae diagnosis relies on culture, serology,
and NAAT [
]. However, isolation requires up to
3 weeks incubation, limiting the practicality of this
method in a clinical setting [
40, 41, 38, 45
time is also a limiting factor for serology, as it is
dependent on a convalescent serum sample [
Moreover, M. pneumoniae has been shown to persist within
the host, with persistent IgM detectable years after
38, 41, 42, 45–50
]. Furthermore, due to the fact
that up to 20% of healthy individuals do not develop M.
pneumoniae-specific IgM combined with the impaired
immune response associated with HIV infection,
immunosuppressed HIV-infected patients may never
develop a detectable antibody response altogether, which
means this technique is not reliable for diagnosis in this
]. In fact, Shankar et al.  found
that culture was more reliable for diagnosing M.
pneumoniae infections in HIV-positive individuals since it
was able to identify infections in 31% (n = 31) of their
adult HIV population, while IgM enzyme-linked
immunosorbent assay only identified 21% (n = 21),
highlighting that relying solely on serology could lead to
a false negative. Consequently, multiple laboratories have
developed NAAT methods (e.g. the BioFire FilmArray
NAAT, or real-time PCR) for the detection of M.
pneumoniae, although the Center for Disease Control and
Prevention has indicated that few of these developed
methods are actually acceptable for diagnostic
37, 44, 52
]. Nonetheless, these amplification
techniques have demonstrated higher sensitivities and
specificities compared to other diagnostics and have
emerged as the new standard for M. pneumoniae
pneumonia detection in HIV [
Coxiella burnetii (Q fever) is an obligate intracellular
bacterium capable of causing acute and chronic illnesses
in both immunocompromised and immunocompetent
individuals alike [
]. However, reports of
HIVassociated Q fever pneumonia are currently limited. Of
those that have been reported, majority of them are from
the pre-cART era [
25, 30, 53, 54
information from the pre-cART era allows us to make inferences
as to how C. burnetii will affect untreated HIV-infected
patients, and those that have previously been treated
with cART but have already progressed to AIDS.
In the 1990s, Q fever pneumonia rates were 0.3% in
the general population and 9.7% in the untreated
HIVseropositive adult population. During this time,
HIVinfected individuals were reported to be 13 times more
likely to contract Q fever than healthy individuals [
Like the other atypical pneumonias, the clinical course
of C. burnetii pneumonia is similar in both HIV-positive
and negative individuals [
]. Symptoms can last up to
10 days and are often non-specific (e.g. fever, headache,
non-productive cough, myalgia); however, in 90% of
cases involving HIV, lung nodules have been shown to
Diagnosing HIV-associated Q fever pneumonia can be
quite challenging due to the many clinical forms of the
disease (e.g. acute or chronic pulmonary infection) and
to the decreasing immunity associated with HIV [
Diagnosis is based on serology and NAAT, however the
potential of false negatives seen in serology increases
with HIV disease advancement [
25, 30, 54
]. Moreover, in
Q fever endemic areas, single serum samples may result
in false positives, thus convalescent serum samples may
be required. NAAT, and, more specifically, PCR—a more
promising alternative with high specificity—are not
widely available [
]. Due to the lack of knowledge
regarding when to test for HIV-associated Q fever
pneumonia, C. burnetii diagnostics in HIV-infected patients
are infrequently attempted and are likely to be
30, 54, 57
The opportunistic intracellular pathogen Legionella
pneumophila is a particular problem in
immunosuppressed patients, and is estimated to be responsible for
20% of all adult HIV-associated pneumonias
(compared to 15% in the general population), although
surprisingly very few cases have actually been reported to
]. Of the cases that have been recorded,
many have shown that HIV-infected patients
(particularly those with advanced immunosuppression) often
present with a more severe clinical presentation
compared to normal individuals [
4, 58, 65
In general, L. pneumophila pneumonia symptoms are
non-specific with significantly higher rates of cough,
dyspnea, bilateral pulmonary involvement, and
hyponatremia in people with HIV [
58, 62, 66, 67
atypical manifestations involving the gastrointestinal
tract or the central nervous system may also occur,
making initial diagnosis quite challenging [
62, 66, 67
Recurrent lung cavitation has been shown to occur almost
exclusively in immunosuppressed patients and often
occurs shortly after initiation of therapy [
58, 60, 68
Complications due to respiratory failure and higher mortality
rates have also been seen .
L. pneumophila infections may be underrepresented in
the HIV population due to the fact that routine
screening for Legionella is not usually performed and requires
a special request from the clinician [
HIV-associated L. pneumophila pneumonia has
traditionally been reliant on culture and the urinary antigen
]; however, culture requires specialized media,
several days for growth, and still only has about 80%
]. For serology, depending on the severity
of the patient’s immunosuppression, measurable L.
pneumophila antigen may not be detectable initially, resulting
in a false negative for the urinary antigen test [
a case by Franzin et al. , a negative urinary antigen
result postponed L. pneumophila diagnosis in a
cARTadhering, HIV-infected adult male until cultures were
obtained (several days later). Thus, definitive diagnosis
of HIV-associated L. pneumophila pneumonia has been
reliant on two methods, both known to have their own
respective limitations [
]. Consequently, NAAT
has become the new standard in diagnostics.
Realtime PCR methods, targeting the Legionella mip gene,
are considered to be more specific, sensitive and rapid
compared to traditional diagnostics (with
approximately a 15% increased yield over culture) and have
been adapted for use in multiple laboratories; however,
in developing nations, these automated techniques are
not readily available [
17, 71, 72
]. Lastly, HIV patients
are often co-infected with more than one pathogen
which could mask infection with L. pneumophila.
Consequently, L. pneumophila may play a much larger
role in HIV-associated pneumonia than is currently
Pneumonia by other non-pneumophila Legionella species
accounts for 10% of all legionellosis in the general
population (with Legionella micdadei and Legionella bozemanae
accounting for 90% of these cases) with limited information
regarding these infections in HIV. However, of the
information that has been gathered, it seems that cART-adhering
HIV-infected individuals have higher rates of
nonpneumophila pneumonia than healthy individuals [
In both treated and untreated HIV, Legionella
nonpneumophila infections commonly manifest as fever, cough,
dyspnea, diarrhea, pleuritic chest pain, and effusion, with
documented instances of pulmonary cavities, nodules, and
lung abscesses [
]. Studies from the pre-cART era
indicate that higher mortality rates are associated with
infection in untreated HIV, although this may be due to the
fact that these infections have only been reported in
severely immunosuppressed patients and may not be due to
the virulence of the microbes themselves [
Diagnosis of HIV-associated non-pneumophila
Legionella pneumonia requires high clinical suspicion. Until a
definitive diagnosis is reached, aggressive empirical
therapy should be administered, especially in
immunodeficient patients, in order to ensure a more positive outcome.
Indeed, discontinuing empiric therapy in an
immunocompromised adult HIV-infected individual despite a high
suspicion of Legionella infection can lead to fatality [
Currently, culture is the best at diagnosing
nonpneumophila pneumonia in HIV; however, sensitivities
vary depending on the laboratory, with higher
sensitivities having only been recorded in laboratories with a
special interest in legionellosis [
73, 75–77, 80, 81
Urinary antigen, although useful for L. pneumophila
serogroup 1 detection, is less sensitive for other serogroups
and is practically useless for non-pneumophila species
]. NAAT methods, specifically PCR of lower
respiratory tract specimens, have demonstrated high
sensitivities (up to 100%) with Legionella species and
may be a possible alternative for detecting
nonpneumophila Legionella pneumonia in HIV-infected
patients. However, although PCR assays can detect all of
the various Legionella species with high specificity, they
are currently not readily available for clinical use [
Little is known about non-pneumophila pneumonia and
its prevalence in HIV, which may simply be due to the fact
that L. pneumophila serogroup 1 is typically the only
Legionella species that is often considered; the urinary
antigen test targets L. pneumophila serogroup 1 and so
do many serological assays [
]. The distribution of
Legionella varies globally, therefore the usefulness of the
urinary antigen test should be validated in each locale
]. Moreover, HIV-associated legionellosis due to
non-pneumophila is similar to L. pneumophila, which
could prevent differentiation between these infections. To
better determine the role of these pathogens in HIV
infection, further development of more appropriate diagnostic
techniques and increased clinical awareness are required.
Tropheryma whipplei, although not usually considered
one of the atypical bacteria, has been found in respiratory
samples of treated HIV-infected individuals at higher
prevalence rates than the general population [
it is unclear whether T. whipplei is a pneumonia-causing
pathogen or merely a commensal organism, since it has
been found in both symptomatic and asymptomatic cases
]. Although some studies report T. whipplei
as a pathogen (and even attribute certain clinical
manifestations to this bacterium), caution is required until more
evidence is acquired about the role of this microbe in
Treatment of atypical bacterial pneumonia in HIV
Unlike typical bacterial pneumonia, atypical bacterial
pneumonia does not respond to beta-lactams,
aminoglycosides, and sulfa drugs; therefore, a 7–10 day course of
macrolides (clarithromycin, erythromycin, or
azithromycin), doxycycline and/or fluoroquinolones (levofloxacin
or moxifloxacin) are required to treat these infections in
HIV patients [
29, 57, 62, 66, 91
Bacterial pneumonia is an immense problem among
immunocompromised HIV-infected individuals,
contributing to the high morbidity and eventual death of these
patients. Although a large proportion of pneumonia is
attributable to typical bacterial infections, clinicians
must be aware of other relevant pathogens, such as C.
pneumoniae, M. pneumoniae, C. burnetti, Legionella
species, and, possibly, T. whipplei.
Diagnosing HIV-associated atypical pneumonia
remains a challenging task and becomes even more so
when the patient is severely immunocompromised. Due
to the lack of data, the lack of consideration, and the
current subpar diagnostic methods, atypical bacterial
pneumonia is often left undiagnosed in HIV-infected
individuals. Studies using more invasive methods (e.g.
bronchoscopy and BAL) may provide a more accurate
depiction of pneumonia. Further studies, and the
development of more appropriate diagnostic methods, are
required to clarify the role and prevalence rates of
atypical bacterial pneumonia in HIV.
AIDS: Acquired immunodeficiency syndrome; BAL: Bronchoalveolar lavage;
cART: Combination antiretroviral therapy; HIV: Human immunodeficiency
virus; IFA: Immunofluorescence assay; MIF: Microimmunofluorescence;
NAAT: Nucleic acid amplification techniques; PCR: Polymerase chain reaction
This project is supported by funding from Colciencias (grant number:
111571249880). The funder had no role in the preparation of the manuscript
nor the decision to publish.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or
analysed during the current study and all information obtained during this
literature search is publically available through PubMed.
BH conducted the literature search as well as drafted the review manuscript.
BH also consulted with AT, ZR, LV and YK, for guidance, editing and to
critically revise the intellectual content of the manuscript. All authors read
and approved the final manuscript.
Ethics approval and consent to participate
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