[Note: james.r.baker@uth.tmc.

edu]
PBL Case 1
Important Findings:
● Shortness of breath
● Pleuritic chest pain x2 wks (which means the pain is worse with breathing)
● Productive cough w/ clear sputum
● Night sweats
● Fever
● Fatigue
● Unprotected sex 2-3x
● Recreational drugs (IV drugs?)
● Nutrition deplete
● No other family members have had recurrent infections like Grant (so if inherited, it
would be recessive)
● Short stature and low body weight
● Bronchial breath sounds at right lung base → bronchi are constricted (indicates chronic
inflammatory process like CF)
● Egophony in RU and RM lobe areas
● Significant drop in oxygenation w/ 6-minute walk test (likely dropped to 90% or less if
they bothered mentioning it)
● WBC count is high → indicates bacterial infection
○ [The rest of his bone marrow function is good, indicated by normal Hematocrit &
Platelet counts]
● Chest x-ray shows demarcation between lower and upper lobe → consolidated infiltrate
in R upper lobe (things like pneumococcus could cause this)
● CT shows extensive airspace opacification of RU and RM lobes
● Mild bronchiectasis (physical collapse of airways b/c of loss of integrity; occurred before
infection)
● Bronchoalveolar-lavage fluid: negative for acid-fast bacilli (knocks some things off DDX -
didn’t get which ones); negative for Pneumocystis jirovecii
● Negative PPD test
● Little improvement after 5 days w/ cefepime, clindamycin, and azithromycin (covers
atypicals and strep)
● Lung biopsy revealed necrotizing granulomas
● Culture of tissue specimen of lung biopsy positive for Burkholderia cepacia, an organism
associated w/ pulmonary infections in patients w/ CF
● Mycobacteria & fungi stains negative
● Sweat chloride test was normal; negative for abnormal CFTR gene on gene panel
● BAL fluid cultures returned negative (for acid-fast bacilli and Pneumocystis jirovecii)
● Negative for HIV infection on screening
● Serum IgA, IgG, and IgM in normal range
● Complement in normal range
● CD4 count in normal range
Active (and inactive) problems:
● Active
○ Shortness of breath
○ Pleuritic chest pain
○ Productive cough w/ clear sputum
○ Night sweats
○ Fever
○ Fatigue
○ Pustular lesions on back & thighs
○ Egophony in RU and RM chest areas
○ Bronchial breath sounds in R lung base → bronchi are constricted (indicates
chronic inflammatory process like CF)
○ X-ray shows extensive opacification of RU and RM lobes
● Inactive
○ Hx of chest colds x10 yrs
○ 2x community-acquired pneumonia (70% Streptococcus pneumoniae
[pneumococcus]; Haemophilus influenzae; Mycoplasma pneumoniae; Legionella
sp)
○ Hx of pustular skin infections on back/thighs → bacterial infections (staph aureus,
staph epidermidis, strep viridans, and strep pyogenes) cause pustular infections
○ Productive cough w/ clear sputum

DDX (including pathophysiology, mechanisms of disease, classification scheme, epidemiology

of the disease, appropriate diagnostic evaluation, optimum disease management for each DX):
● Congenital or acquired immuno compromised
○ HIV
■ Not supported b/c no cervical lymphadenopathy
■ Not supported because negative for Pneumocystis jirovecii (opportunistic
pathogen)
■ Not supported by negative HIV screening test
■ Not supported by high-normal CD4 counts
○ Chronic granulomatous disease
● Infectious etiologies
○ TB
■ Not supported b/c no cervical lymphadenopathy
■ Not supported b/c negative PPD test, so never been exposed to Tb
○ Viral (upper respiratory infection)
○ Bacterial
■ Not supported because negative stains in lung biopsy
○ Fungal
■ Not supported because negative stains in lung biopsy
● Structural lung abnormality
○ Cystic fibrosis
 ■ Not supported b/c wouldn’t develop this late, and more likely a systemic
problem than anatomic abnormality of the lung b/c of the skin infections
■ Not supported by the bronchoscopy
■ Not supported by normal sweat chloride test
■ Not supported by negative abnormal CFTR gene panel
■ Not supported by no family history (although that wouldn’t be enough
alone to exclude it)
■ Supported by tissue specimen obtained during lung biopsy positive for
Burkholderia cepacia
○ Collagen vascular process - scleroderma, variant of RA, lupus, sarcoidosis (but
usually middle aged African American women), noxious chemical causing
irritation of lung
● Pulmonary embolism
● Hemothorax
● Drug-induced lupus
○ Not supported b/c would suspect more systemic finding instead of just lung
● Malignancy
○ Not supported b/c no cervical lymphadenopathy
● Chronic Granulomatous Disease
○ Supported by
■ Tissue specimen obtained during lung biopsy positive for Burkholderia
cepacia
■ DHR oxidation test - neutrophil oxidative index (NOI) is very low,
indicating lack of oxidative burst in response to stimulation
■ Mother is a carrier and it is X-linked
■ No hepatosplenomegaly
■ No anemia
■ No hypergammaglobulinemia

Diagnosis Plan:
● Physical exam
● X-ray
● Sputum culture (have them cough to get a sample of the secretions or if they can’t, use a
bronchoscope)
● CBC
○ [If testing antibodies, that would be in a second round of testing]
● Peripheral smear - morphology of WBC (percentage of lymphocytes, basophils,
eosinophils, etc.)
● PPD skin test for Tb (w/ control [mumps or candida])
● Sweat chloride test to rule out CF
● Testing antibodies
● Test for chronic granulomatous disease - DHR (dihydrorhodamine)

Treatment Plan for Chronic Granulomatous Disease:

 ● Prophylaxis against:
○ Bacteria (susceptible to catalase + [Mnemonic: Cats need places to hide]; also
want to cover opportunistic infections)
■ TMP-SMX
○ Fungus
■ Itraconazole (prophylaxis for Aspergillus)
○ Boost immune system
■ Gamma-IFN
● Bone marrow stem-cell transplant
● Provide education on the importance of a healthy diet for immune system function

Telling Patient:
● Ask if he wants mother in the room
● Could bring genetic counselor to give info for if he wants to have kids

Learning Issues:
● Diagnosis of pleuritic chest pain?
● Pathophysiology of SOB - Kyle
● Egophony, tactile fremitus,whispered pectoriloquy - Angela
● Clindamycin coverage and whether it will kill Burkholderia cepacia - Miranda
● Azithromycin coverage and whether it will kill Burkholderia cepacia - Andrew
● Cefepime coverage and whether it will kill Burkholderia cepacia - Zachary
 Pathophysiology of Shortness of Breath - Kyle

The pathway of the communication of air hunger to the brain begins along two main pathways.

The first is both central and peripheral chemoreceptors. Central chemoreceptors, located on the

ventral surface of the medulla, detect a low pH in the CSF which is a proxy for excess arterial

CO2 due to the fact that while H+ cannot cross the blood brain barrier, CO2 can cross and once

it does it combines with water to ultimately form bicarbonate and H+. While these central

chemoreceptors only detect PaCO2, peripheral chemoreceptors located in the aortic and carotid

bodies detect changes in both O2, CO2, as well as H+ levels directly in the arterial blood. The

second pathway concerns mechanoreceptors located in the lungs (although some are found

within muscle and joints and are associated with exercise). These mechanoreceptors detect

stretch of various parts of the lung and regulate respiration rate accordingly. These receptors

send their signal to the brainstem (the pons and medulla) via both the glossopharyngeal

(peripheral chemoreceptors) and the vagus (peripheral chemoreceptors and lung

mechanoreceptors) nerves where 3 major controllers of respiration exist. The first is the

medullary respiratory center which sets the basic rhythm of respiration. The second is the

apneustic center, which prolongs inspiration by stimulating the inspiratory portion of the

medullary respiratory center. The last is the pneumotaxic center, which inhibits inspiration to

regulate breathing rate. Once the respiration rate and rhythm has been set the medullary

respiratory center then communicates this set point to the diaphragm via the phrenic nerve. It is

also finally worth noting that these brain stem centers can be consciously affected by an

individual via communication from the cerebral cortex.

Source:

Costanzo, Linda S. Physiology. , 2018. Online.

 Egophony - Angela

What is it:
● A physical examination technique where you ask the patient to say “ee” while auscultating in
symmetric areas over their chest wall and lung fields
● If ee sounds like ee upon auscultation, this is normal
● If “ee” sounds like “a,” this is egophony. The “A” should be localized

Significance
● Aids in the clinical differential diagnosis process
● For example: if a pt comes in with a cough, fever, and bronchial breath sounds (screening
items for pneumonia), you can check for the presence of egophony to support your hypothesis
for lobar pneumonia. In fact, the presence of egophony more than triples the likelihood of
pneumonia
● Abnormal resonance- be suspicious for pneumonia, pleural effusion, pulmonary edema,
pulmonary hemorrhage
Tactile Fremitus

What is it:
● Normal lungs transmit a palpable vibratory sensation on the chest wall (fremitus). Detect this
by placing ulnar surface of both hands against either side of chest wall and posterior thorax
and ask patient to say 99. Check for symmetry in the transmitted vibrations

Significance
● Lung consolidation increases transmission of sound and fremitus becomes more pronounced
in cases of lobar pneumonia, pulmonary edema, pulmonary hemorrhage
● Pleural effusion- fluid space can collect in the potential space between lung and chest wall
displacing the lung upwards leading to asymmetric decreased fremitus over the area of
effusion. Can also be seen in neoplasm (infiltrating tumor), COPD, fibrosis, and
pneumothorax.
Whispered Pectoriloquy
What is this:
● A physical exam technique where you ask the patient to whisper 99 or 123 while auscultating
symmetric lung fields
● In normal findings the whispered voice is faint and indistinct but if you hear louder, clearer,
whispered sounds, this is called whispered pectoriloquy
● Increase in sound happens because sound travels faster through liquid or solid

Significance
● Pt. with lung consolidation will have presence of whispered pectoriloquy

Source: Bate’s Guide to Physical Examination and History Taking

Clindamycin - Miranda
 ● Acts on the bacterial 50S ribosomal subunit, inhibiting peptide transfer (translocation) →
inhibiting protein synthesis; Bacteriostatic (Le et al. 2017; Sketchy Medical)
● Overview of coverage: Gram + bacteria including Staph (CA-MRSA) and Strep (Strep
pyogenes [GAS]); Anaerobes including Clostridium (Clostridium perfringens) and
Bacteroides (Bacteroides fragilis) (Sketchy Medical)
● Clindamycin coverage (Pham and Bartlett, 2015) [Note: 1st line against underlined
bacteria; All others are 2nd line]
○ Aerobic gram-positive bacilli: Arcanobacterium (haemolyticum), Bacillus cereus,
Bacillus spp (not anthracis or cereus), Propionibacterium acnes,
Corynebacterium diphtheriae
○ Aerobic gram-positive cocci: Leuconostoc spp, Staphylococcus aureus
(methicillin-sensitive), Streptobacillus moniliformis, Streptococcus (Group G),
Streptococcus (Group C), Streptococcus agalactiae (Group B), Streptococcus
pneumoniae, Streptococcus pyogenes (Group A), Streptococcus intermedius
group (S. anginosus, S. intermedius, S. constellatus)
○ Anaerobic gram-positive bacilli: Actinomyces israelii, Actinomyces naeslundii,
Actinomyces odontolyticus, Arachnia propionica, Clostridium spp., Lactobacillus
spp.
○ Anaerobic gram-positive cocci: Peptostreptococcus spp., Viridans streptococci
○ Miscellaneous: Chlamydia trachomatis, Mycoplasma spp.
○ Spirochete: Leptospira interrogans, Spirillum minus
○ Aerobic gram-negative bacilli: Campylobacter jejuni, Capnocytophaga
canimorous (DF-2), Capnocytophaga ochracea (DF-1),
Chryseobacteriummeningosepticum, Gardnerella vaginalis
○ Anaerobic gram-negative bacilli: Prevotella bivia (Bacteroides), Bacteroides
distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, Bacteroides vulgatus, Leptotrichia buccalis, Prevotella
intermedius, Fusobacterium necrophorum, Prevotella melaninogenicus
● Burkholderia cepacia
○ Catalase+, Gram-negative, non-spore-forming bacilli (Eshwar et al. 2005)
○ Opportunistic human pathogen that most often causes pneumonia or serious
respiratory infections in immunocompromised individuals or people with chronic
lung diseases (cystic fibrosis; chronic granulomatous disease) (CDC 2016;
Eshwar et al. 2005)
○ Often resistant to common antibiotics (CDC 2016; Eshwar et al. 2005)
Sources:
1. “Burkholderia Cepacia in Healthcare Settings.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention,
27 June 2016, www.cdc.gov/hai/organisms/bcepacia.html
2. Le, Tao, et al. “Microbiology.” First Aid for the USMLE Step 1 2017, McGraw Hill Education, 2017, pp. 118.
3. Mahenthiralingam, E., Urban, T. A., & Goldberg, J. B. (2005). The multifarious, multireplicon burkholderia cepacia complex. Nature
Reviews. Microbiology, 3(2), 144-56. doi: http://dx.doi.org.ezproxyhost.library.tmc.edu/10.1038/nrmicro1085
4. Pham, Paul A, and John G Bartlett. “Clindamycin.” Johns Hopkins ABX Guide, Johns Hopkins Medicine, 14 Dec. 2015,
www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540131/all/Clindamycin.
5. Sketchy Medical Video - Clindamycin
 Azithromycin - Andrew
Azithromycin is a second generation macrolide which broad-spectrum antibacterial
activity. It is a 15-membered lactone ring azalide that shares the same mechanism of action with
other macrolides but is able to accumulate more effectively in phagocytes which allows it be
administered in higher concentrations. It has a longer half-life in tissues allows it to be more
effective in a single dose. Azithromycin inhibits bacterial protein synthesis by binding to and
interfering with the 50S subunit. It also works by inhibiting the generation of both growth-
stimulating compounds, quorum-sensing compounds, and alginate biofilm which protects the
micro-organism from antibiotic actions. Azithromycin also has immunomodulatory effects.
Azithromycin is a basic compound and this basicity allows it to penetrate the outer membrane
faster and more effectively targeting Gram-negative bacteria. Bacterial resistance occurs in two
ways: 1. Mutations of some ribosomal components including changing the target and/or binding
site and 2. Increase efflux pump activity. Azithromycin is not metabolized or inhibit CYP3A4 and
so it is free of drug interactions and excreted by the hepato-biliary system. Azithromycin has an
increase rate of cardiovascular death and increased rate of arrythmias in at risk patients
(obese), but is otherwise safe.
Uses:
● Upper respiratory tract infections: S. pyogenes, Streptococcus pneumoniae,
Mycoplasma pneumoniae, Chlamydia spp., Legionella pneumophila, Niesseria
gonorrhoeae, Bordatella pertussis, Campylobacter jejuni, Treponema pallidum,
Ureaplasma urealyticum, Corynebacterium diphtheria, Listeria monocytogenes,
Haemophilus influenza, Moraxella catarrhalis, non-tuberculosis mycobacteria, Bartonella
henselae, Rhodococcus equi, Toxoplasma spp., Cryptosporidium spp.,Plasmodium
species, H. influenzae, M. catarrhalis, S. pneumonia.
● Lower respiratory tract infections (LRTI)- community-acquired pneumonia and acute
bacterial sinusitis
● Not bacteriacidal against Pseudomonas aeruginosa but can inhibit its virulence factor
production and can be used prophylactically.
● Diffuse panbronchiolitis, cystic fibrosis and non-cystic fibrosis bronchiectasis, chronic
obstructive pulmonary disease, asthma
● Post-transplant bronchiolitis
● First line treatment in many causes of Urethritis: Chlamydia trachomatis, Ureaplasma
urealyticum, mycoplasma genitalium.
● Chronic bacterial prostatitis: becoming primary option
● STD’s: syphilis, granuloma inguinale (first-line), chancroid (first-line)
● Glomerulonephritis from Gram-positive or Gram-negative Bartonella species
● Sepsis: Random control trials indicate how impactful Clarithromycin is suggests the
impact Azithromycin may have
● Others: Skin disease, dentistry (periodontal disease, gingival overgrowth),
ophthalmology (bacterial conjunctivitis), gastric motility
● Burkholderia cepacia: no effective against this but in an in vitro study synergistic activity
with Azithromycin-trimethoprim-sulfamehtoxazole, azithromycin-ceftazidime, and
azithromycin-doxycycline inhibited ~20% of Burkholderia cepacia.
Sources:
Parnham, Michael J., et al. “Azithromycin: Mechanisms of action and their relevance for clinical applications.” Pharmacology &
Therapeutics, vol. 143, no. 2, Aug. 2014, pp. 225–245., doi:10.1016/j.pharmthera.2014.03.003.
Saiman, Lisa et al. “Synergistic Activities of Macrolide Antibiotics against Pseudomonas Aeruginosa, Burkholderia Cepacia,
Stenotrophomonas Maltophilia, and Alcaligenes Xylosoxidans Isolated from Patients with Cystic Fibrosis.” Antimicrobial Agents and
Chemotherapy 46.4 (2002): 1105–1107.PMC. Web. 10 Jan. 2018.
 Cefepime Coverage- Zach

● 4th generation cephalosporin

● Binds to PBPs halting peptidoglycan wall synthesis
● Penetrates the CNS (can treat meningitis)
● Used for serious systemic infections especially for patients at risk for multidrug resistant
organisms
● Coverage:
○ Active against Gram - species such as H. flu, Neisseria species, and
pseudomonas
○ Active against Gram + species such as Staph and Strep species
○ “In general, Burkholderia manifests innate resistance to aminoglycoside
antibiotics and widespread resistance to many beta-lactam agents, including
extended-spectrum penicillins such as piperacillin and the 4th generation
cephalosporin cefepime.[2] … However, our findings indicate that Burkholderia
spp. isolated from cancer patients may manifest an antibiogram different from
that usually observed, by retaining susceptibility to more number of antibiotics
especially to piperacillin-tazobactam and cefepime.”
Sources:
● Sketchy Medical
● Roy P, Ahmed NH, Biswal I, Grover R. Antimicrobial Susceptibility Pattern of
Burkholderia cepacia Isolates from Patients with Malignancy. Journal of Global
Infectious Diseases. 2014;6(2):90-91. doi:10.4103/0974-777X.132064.
 Case Objectives
1.
2.
3.
4.
5. Catalase + and aspergillus
6. Washing hands, diet, …
7. X-linked, so mostly males, also AR variant
8. Gene therapy - modify genes in vivo; stem cell transplantation - wipe out and replace
9.
10.
11.