Man With Severe Dyspnea, Fever, and Cough

December 31, 2006

A46-year-old white man is hospitalized with increasing dyspnea of 3weeks’ duration. He has a history of stable chronic obstructive pulmonarydisease secondary to heavy smoking (2 packs of cigarettes a day for 27years, discontinued 6 years previously) and uses inhaled bronchodilators.

A 46-year-old white man is hospitalized with increasing dyspnea of 3weeks' duration. He has a history of stable chronic obstructive pulmonarydisease secondary to heavy smoking (2 packs of cigarettes a day for 27years, discontinued 6 years previously) and uses inhaled bronchodilators.During the past month, he has complained of exhaustion and has lostnearly 9 kg (20 lb). He has had a dry, irritating cough and fever with rigorsnearly continuously for the past week. His dyspnea developed graduallybut has progressed to such an extent that he is unable to walk a few feet onlevel ground and was unable to talk in full sentences when first seen in theemergency department.There is no history of chest pain, hemoptysis, palpitations, paroxysmalnocturnal dyspnea, orthopnea, or ankle edema. The patient had intermittentwatery diarrhea for a week at the onset of his illness. He has no adenopathyor joint swelling. He has had no contact with ill persons or exposure to tuberculosis.A 10-day course of levofloxacin was prescribed, but the patient'scondition did not improve. History. The patient does not drink alcohol, has never taken recreationaldrugs, and has had no blood transfusions. He is married but has been sexuallyinactive for the past 3 years. He has a history of cutaneous allergic reactionto penicillin.Examination. This lean man is in moderate respiratory distress, evenwith nasal oxygen. Temperature is 38.8C (102F); heart rate, 125 beats perminute and regular; blood pressure, 118/76 mm Hg; respiration rate, 28breaths per minute; and weight, 50 kg (110 lb). There is no evidence of anemia,clubbing, cyanosis, icterus, or thrush. Thyroid is not palpable; there areno rashes or tattoos. Examination of respiratory system reveals emphysematouschanges; both sides of chest move equally well. Trachea is centrally located.Chest is resonant to percussion. Harsh bronchovesicular sounds areaudible bilaterally, with prolonged expiration and bilateral rales, particularlyat the bases. Jugular vein pulse is normal; peripheral pulses are easily felt.Cardiac impulse is within normal limits. Heart sounds are normal, with nogallop or murmur. Abdomen is soft and benign, with no organomegaly ortenderness. Results of the neurologic examination are unremarkable.Laboratory studies. White blood cell (WBC) count is 4000/μ L, with65% polymorphonuclear leukocytes, 32% lymphocytes, and 3% monocytes.Hemoglobin level, 11.8 g/dL; platelet count, 186,000/μ L; erythrocyte sedimentationrate, 112 mm/h. Urine, clear. Blood urea nitrogen level, 12mg/dL; serum creatinine, 0.9 mg/dL. Serum sodium, 134 mEq/L; potassium,4.1 mEq/L; chloride, 100 mEq/L; bicarbonate, 24 mEq/L; serum albumin,2 g/dL; total bilirubin, 1.1 mg/dL; and blood glucose, 98 mg/dL. Aspartateaminotransferase level, 22 IU/L; alanine aminotransferase, 18 IU/L;and lactate dehydrogenase (LDH), 575 IU/L. Total cholesterol level, 164mg/dL; low-density lipoprotein cholesterol, 112 mg/dL; and high-densitylipoprotein cholesterol, 45 mg/dL. β-type natriuretic peptide, 13.8 pg/mL.Arterial blood gases: pH, 7.49; PaCO2, 25 mm Hg; PaO2, 50 mm Hg; oxygensaturation (SO2, ), 89% on 2 L of oxygen. An ECG shows sinus tachycardia.
You order a chest radiograph.Which of the following pathogens do you suspect caused theabnormalities evident on this film? A. Streptococcus pneumoniae B. Staphylococcus aureus C. Coccidioides immitisD. Pneumocystis jiroveciiE. Legionella pneumophilaWHAT'S WRONG:
The chest film shows emphysematous lungs witha diffuse bilateral ground-glass interstitial infiltrate. Ina man with increasing dyspnea, dry cough, weight loss,and night sweats who has severe hypoxemia, leukopenia,and an elevated LDH level, these radiographicfindings strongly suggest infection with Pneumocystisjirovecii, D.Hospital course. A CT scan of the chest revealedsevere bullous emphysema with diffuse interstitial infiltrate.A gram-stained sputum specimen showed rareWBCs. No organisms were grown on cultures. Repeatedacid-fast bacillus (AFB) tests were negative, and atuberculin skin test was nonreactive. A urinary Legionellaantigen test and culture for Hantavirus and influenzavirus were negative. Mycoplasma, Chlamydia, andToxoplasma titers were normal. Bronchoscopy withbronchoalveolar lavage (BAL) revealed foamy exudatethat did not contain AFB or fungal elements, and theresults of the culture were negative. An open lung biopsyshowed several pneumocystic organisms.Additional test results included a CD4 cell countof 39/μL and a positive HIV test (enzyme-linked immunosorbentassay and Western blot). HIV viral load,320,510 copies/mL. Rapid plasma reagin test, negative;hepatitis panel, negative; and stool examination, negativefor ova and parasites. Further inquiry revealedthat the patient had a remote history of sexual activitywith numerous homosexual partners, some of whomwere HIV-positive.The patient was treated initially with nasal oxygen,ceftriaxone, and azithromycin. Once the diagnosiswas confirmed, treatment was switched to IV trimethoprim-sulfamethoxazole (TMP-SMX), 15 mg/kg/d in3 divided doses, with methylprednisolone sodium succinate,125 mg once a day for a week.His respiration improved considerably with improvementof blood gases: pH, 7.42; PaCO 2, 21 mmHg; PaO2, , 84 mm Hg; and SO2, , 94%. After a week, intravenousTMP-SMX was changed to the oral formulationand he was given a combination of zidovudine,300 mg, and lamivudine, 150 mg, twice a day, plus atazanavir,400 mg once a day. His opportunistic infectionprophylaxis included azithromycin, 1200 mg once aweek, and fluconazole, 200 mg once a day. He will befollowed regularly in the outpatient department.OVERVIEWPneumocystis jirovecii (formerly Pneumocystiscarinii) pneumonia (PCP) is a common opportunisticrespiratory infection and a major source of morbidityand mortality in immunocompromised patients. It ismost frequently encountered in persons with defects incell-mediated immunity as a result of hematologic malignancies,lymphoproliferative diseases, cancer therapy, orAIDS. About 30% of patients with HIV infection havePCP as the initial AIDS-defining illness. More than 80%of AIDS patients with CD4 cell counts below 200/μLcontract this infection if not treated prophylactically.However, the incidence of PCP in HIV-infected patientsin developed countries has decreased dramatically since1998, as a result of administration of primary prophylaxisto patients in this group and the widespread adoptionof HAART.P jirovecii is a ubiquitous unicellular organism. Thetaxonomic classification (fungus or protozoan) is still uncertain.The organism was first isolated in guinea pigsby Chagas and then by Carini in the early 1900s. Thefirst cases of active Pneumocystis infection were seen inpremature and malnourished children in Europe duringWorld War II.P jirovecii exists in 3 morphologic forms:

  • Cysts: round or crescent-shaped, 5 to 8 μm in diameter,and covered by a 3-layer pellicle (Figure).

  • Sporozoites: these are present within the cysts. A maturecyst can contain up to 8 sporozoites, which areround or crescent-shaped intracystic structures 1 to2 μm in diameter.

  • Trophozoites: free-floating forms of Pneumocystis,which are usually 2 to 5 μm in diameter and pleomorphic.They resemble platelets and tend to form clusters.


The primary mode of transmission of Pneumocystisis thought to be via inhalation of airborne cysts that subsequentlycolonize the respiratory tract. Most Americansshow evidence of seroconversion by age 3 years. Only immunocompromised persons have signs of clinical diseasewith probable reactivation of the latent infection.High-risk groups include:

  • Patients infected with HIV whose CD4 cell count isless than 200/μL and who are not receiving PCP prophylaxis;who have evidence of oropharyngeal candidiasis,unexplained persistent fevers, or weight loss; or whohave undergone splenectomy.
  • Patients with hematologic malignancies.
  • Patients who are receiving long-term corticosteroidor immunosuppressant therapy, including those withsystemic vasculitis or autoimmune diseases.
  • Organ transplant recipients.
  • Patients with thymic hypoplasia, severe combinedimmunodeficiency, or hypogammaglobulinemia.
  • Patients with severe malnutrition.

In HIV-infected patients,


infection is3 times more common in white persons than in AfricanAmericans and twice as common in homosexual or bisexualmen as it is in women.


In more than 75% of patients, PCP manifests withan insidious onset of malaise, weight loss, and low-gradefever that is initially associated with a dry cough (59% to91% of patients). However, the symptoms may be moresevere, and dyspnea (present in 29% to 95% of patients),cyanosis, and respiratory failure (5% to 30%) may bepresent. Chest pain is reported in 14% to 23% and productivecough in 23% to 30% of patients.


Patients receiving prophylaxis with inhaled pentamidinemay present with milder symptoms and an increasedincidence of pneumothorax and extrapulmonarymanifestations, such as unexplained lymphadenopathy,hepatosplenomegaly, and choroid lesions in theabsence of intraocular inflammation.Clinical presentation ranges from severely immunocompromisedpatients who appear very toxic and are inrespiratory distress to those who have fever, tachycardia,and tachypnea--but do not appear toxic--and whosenonfocal lung examination reveals basal rales, signs ofconsolidation, or acute bronchospasm. In 50% of patients,the lung examination results may be entirely normal.


A high index of suspicion is necessary to make thediagnosis, because the clinical picture of PCP resemblesthat of other respiratory tract infections.

Radiographic evaluation.

The preferred modalitiesare chest radiography, CT, and gallium scanning. Initialchest radiographs may be normal in about 25% of patients.The most common abnormalities are bilateral diffuseinterstitial or alveolar infiltrates. Less common findingsinclude pneumothorax, pneumatocele, pleural effusion,and nodular or cystic lesions.High-resolution CT has a sensitivity of 100% and aspecificity of 89%; in patients with PCP, it shows patchyor nodular ground-glass attenuation. Gallium scanninghas 100% sensitivity in patients with PCP; it demonstratesdense, diffuse bilateral uptake.

Laboratory studies.

The following are recommended:

  • LDH level. In patients with PCP, this is usually higherthan 220 IU/L. The test has a sensitivity of 78% to 100%and a specificity of 74%.
  • Pulse oximetry and arterial blood gases typically revealhypoxemia and an increased alveolar-arterial oxygengradient.
  • A routine sputum examination usually does not revealthe organism. A specimen obtained by induction withhypertonic saline, followed by testing for direct fluorescentPneumocystis antibody, may be helpful. This testhas a sensitivity of 55% to 97% and a specificity of 99%to 100%.

Other studies.

If sputum examination results arenegative but suspicion of PCP remains high, proceed tobronchoscopy, BAL, and transbronchial biopsy. Thesetests have a sensitivity of 86% and a specificity of 99% to100%. Occasionally, the diagnosis cannot be establishedconclusively with bronchoscopy and BAL. In this situation,as with our patient, an open lung biopsy is required.


The mainstay of treatment is early diagnosis andtimely, prompt administration of appropriate medications.Persons with mild to moderate disease can be consideredfor outpatient therapy. These patients havemilder symptoms and a nontoxic appearance. They arenot hypoxic and may have normal radiographic results.Persons with moderate to severe disease--thosewith severe respiratory distress, hypoxia, and often amarkedly abnormal chest radiograph--require inpatienttherapy.

Drug treatment.

The agent of choice is oral or intravenousTMP-SMX. If a patient is hypersensitive toor cannot tolerate TMP-SMX, alternative agents may beoffered. These are listed in the


Supportive therapy.

Oxygen supplementation, includingventilatory support, is required in patients withmoderate to severe hypoxia. Corticosteroid therapy isrecommended for those whose PaO


is less than 70 mmHg. It reduces hypoxemia, the need for intubation, andlate fibrosis. The suggested regimen is oral prednisone,40 mg bid for 5 days; 40 mg qd for 5 days; and 20 mg qdfor 11 days.


Prophylaxis against Pneumocystis has greatly decreasedthe incidence of PCP in patients infected withHIV. Primary prophylaxis is initiated in a patient whodoes not have PCP but whose CD4 cell count is lessthan 200/μL, or who has had unexplained persistentfever, weight loss, or oral candidiasis for more than2 weeks. Secondary prophylaxis is initiated after anepisode of PCP. Prophylaxis is discontinued when theCD4 cell count is higher than 200/μL for 3 months.The first-line agent for prophylaxis is TMP-SMX.If a patient cannot tolerate TMP-SMX, dapsone is an acceptablealternative. Aerosolized pentamidine or atovaquoneis used for those who cannot tolerate TMP-SMXor dapsone.


The prognosis for patients with PCP has changeddramatically since the advent of new prophylactic andtreatment modalities. Before 1985, the overall survivalrate was 50%. Currently, the survival rate for patientswith mild to moderate PCP is 86% to 94%. The rate is40% to 50% for patients who require ventilatory support.The best prognostic indicator of survival is the level ofoxygenation.




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