Answers To Case 7 HIV and Pneumocystis Carinii Pneumonia

Summary: A 32-year-old man with known HIV infection but unknown CD4 count presents with subacute onset of fever, dry cough, and gradually worsening dyspnea. He is not undergoing any antiretroviral therapy or taking prophylactic medications. Diffuse bilateral pulmonary infiltrate is seen on chest x-ray. and he is tachypneic and hypoxemic. The presence of oral thrush suggests that he is immunosuppressed. His leukocyte count is decreased, and his LDH level is elevated.

^ Most likely diagnosis: Acquired immunodeficiency syndrome (AIDS) and probable Pneumocystis carinii pneumonia (PCP).'

♦ Next step: The next step is to stabilize the patient, who is tachypneic and hypoxic but is in only mild distress and is hcmodynamically stable. Therefore, there is time to further evaluate him. An arterial blood gas measurement can be obtained to quantify his degree of hypoxemia, as it will impact the treatment.

'As of 2002, the organism has been renamed Pneumocystis jimveci. The abbreviation PCP remains for Pneumocystis carinii pneumonia.

^ What other diagnoses must be considered? In patients with AIDS, other opportunistic infections must be considered. Other respiratory infections, such as tuberculosis (TB), atypical mycobacteria, cryptococcosis, and disseminated histoplasmosis, must be considered. In addition. HIV-infected patients are susceptible to the usual causes of community-acquired pneumonias: Streptococcus pneumoniae, mycoplasma, and viruses such as influenza.

Analysis

Objectives

1. Understand the natural history of HIV infection.

2. Know the types of opportunistic infections that typically affect HIV-infected patients at various levels of immunocompromise.

3. Be familiar with respiratory infections in patients with AIDS.

4. Be familiar with indications for antiretroviral therapy and for prophylactic medications against opportunistic infections.

Considerations

This individual with HIV, currently not taking antiviral medications or any antibiotic prophylaxis, presents with subacute dyspnea and cough. His lack of sputum production and elevated LDH level is suggestive of PCP. The presence of oral thrush suggests a CD4 count <250. If the CD4 count is <200, then PCP seems the most likely explanation for his symptoms and chest x-ray findings. Obtaining an arterial blood gas measurement will provide information about prognosis and help guide therapy. Arterial oxygen concentration <70 mmHg or alveolar-arterial gradient (A-a) >35 mmHg suggests a worse prognosis and corticosteroids may be helpful, followed by treatment with trimethoprim-sulfamethoxazole (TMP-SMX).

Clinical Approach

When evaluating a patient with HIV and suspected opportunistic infection, it is essential to know or estimate the patient's level of immunodeficiency. This is reflected by the CD4 (T4) cell count. Normal CD4 levels in adults range from 600 to 1500 cells/mm3. As levels decline to <500/mm3, immune function is compromised, and patients become increasingly susceptible to unusual infections or malignancies.

Approximately 30% of patients first infected with HIV will develop an acute HIV syndrome characterized by sudden onset of a mononucleosislike illness with fever, headaches, lymphadenopathy, pharyngitis, and sometimes a macular rash. The rest of the patients remain asymptomatic and have a clinically latent period of 8-10 years, on average, before the clinical manifestations of immunocompromise appear. As CD4 levels decline, various opportunistic infections appear. At levels <500, patients are susceptible to infections, such as recurrent pneumonias, TB, vaginal candidiasis, and herpes zoster. At levels <200. patients are significantly immunocompromised and develop infections with organisms that rarely cause significant illness in immunocompetent hosts, such as Pneumocystis jiroveci (formerly Pneumocystis carinii), toxoplasmosis, cryptococcosis, histoplasmosis, or cryptosporidiosis. At levels <50. patients are severely immunocompromised and are susceptible to disseminated infection with histoplasmosis and Mycobacterium avium-intracellulare complex (MAC) as well as development of cytomegalovirus (CMV) retinitis colitis, esophagitis, or primary central nervous system (CNS) lymphoma.

PCP remains the most common opportunistic infection affecting AIDS patients but often is very difficult to diagnose. The clinical presentation ranges from fever without respiratory symptoms, to mild, persistent, dry cough, to significant hypoxemia and respiratory compromise. In addition, the radiographic presentation can be highly variable, ranging from a near-normal chest film to a diffuse bilateral infiltrate, to large cysts or blebs (but almost never causes pleural effusion). The blebs can rupture, causing spontaneous pneumothorax. PCP often is diagnosed presumptively when patients present with subacute onset of fever and respiratory symptoms. Definitive diagnosis can be established by use of Giemsa or silver stain to visualize the cysts but usually requires induction of sputum using aerosolized hypertonic saline to induce cough or bronchoalveolar lavage to obtain a diagnostic specimen. Elevated LDH level often is used as an indirect marker for PCP. although it is nonspecific and may also be elevated in disseminated histoplasmosis or lymphoma. It is useful as a negative predictor because patients with an LDH level <220 IU/L are very unlikely to have PCP. Similarly, if patients have a CD4 count >250/mm3 or if they were taking PCP prophylaxis with TMP-SMX. the diagnosis of PCP should be considered highly unlikely.

The level of oxygenation of PCP patients by arterial blood gas is useful because it may affect prognosis and therapy. Patients with arterial Po2 <70 mmHg or A-a gradient >35 mniHg have significant disease and have an improved prognosis if prednisone is given in conjunction with antimicrobial therapy. After prednisone is given to patients with hypoxia, the usual treatment for PCP is TMP-SMX. Patients who are allergic to sulfa can be treated with alternative regimens, including pentamidine or clindamycin with primaquine.

Many other respiratory infectious are possible and should be considered in patients with AIDS. Diagnosis can be suggested by chest radiography. Diffuse interstitial infiltrates are seen with PCP. disseminated histoplasmosis. Mycobacterium tuberculosis, and Mycobacterium kansasii. Patchy infiltrates and pleural-based infiltrates can be seen with TB and cryptococcal lung disease. Cavitary lesions can be seen with TB. PCP. and coccidiomycosis. Clinical history should also be considered. Because the most common causes of pneumonia in AIDS patients are the same organisms that cause pneumonia in immunocompetent hosts, acute onset of fever and productive cough, with a pulmonary infiltrate, is most consistent with community-acquired pneumonia. A more indolent or chronic history of cough and weight loss, especially in a patient who has a high-risk background (prison, homeless, immigrant), should raise the question of tuberculosis. In patients with CD4 count >200, the radiographic appearance of TB is likely to be similar to that of other hosts, for example, bilateral apical infiltrate with cavitation; in those with CD4 count <200. the radiographic appearance is extremely variable. Because TB involves both the alveoli and the pulmonary circulation, patients with TB rarely are hypoxic with minimal infiltrate on chest x-ray (although this is relatively common in PCP). Patients with suspected pulmonary TB should be placed in respiratory isolation until it is assured they are not spreading airborne tuberculous infection. Diagnosis and treatment of TB is discussed in Chapter 31. In HIV patients. M. kansasii can cause pulmonary disease and radiographic findings identical to those of M. tuberculosis.

Several other opportunistic infections in AIDS deserve mention. Cerebral toxoplasmosis is the most common CNS mass lesion in AIDS patients. It typically presents with headache, seizures, or focal neurologic deficits, and it is seen on CT or MRI scan, usually as multiple enhancing lesions, often located in the basal ganglia. Presumptive diagnosis often is made based on the radiologic appearance, supported by serologic evidence of infection. The major alternative diagnosis for CNS mass lesions is CNS lymphoma. This diagnosis is considered if there is a single mass lesion or if the lesions do not regress after 2 weeks of empiric toxoplasmosis therapy with sulfadiazine with pyrimethamine. If this is the case, historically, the next diagnostic step has been stereotactic brain biopsy. However, recent evidence indicates that examination of the cerebrospinal fluid (CSF) for Epstein-Barr virus DNA is a useful strategy because it is present in >90% of cases of patients with CNS lymphoma.

Another CNS complication that requires a high index of suspicion is crypto-coccal meningitis. It is a chronic indolent infection, which often presents with vague symptoms of mood or personality changes, headaches, or visual disturbance. If the diagnosis is considered, one can screen for evidence of cryptococ-cal infection by a serum cryptococcal antigen or perform a lumbar puncture. CSF frequently shows a lack of inflammatory response (i.e., normal white blood cell |WBC] count), but the patient often presents with elevated intracranial pressures. Diagnosis can be confirmed by demonstrating the yeast by India ink stain, by fungal culture, or by measuring the level of cryptococcal antigen from CSF. Treatment of cryptococcal meningitis requires induction with intravenous amphotericin B plus flucytosine, then chronic suppression with oral fluconazole. At times, frequent lumbar punctures with removal of large volumes of CSF are required to treat the intracranial hypertension, and CSF shunts may be required.

At very low CD4 counts (<50/mm3), patients with AIDS are also susceptible to C\1V infections. This can be manifested as viremia with persistent fever and constitutional symptoms, retinitis that can lead to blindness, esophagitis that can cause severe odynophagia, colitis, and necrotizing adrcuaiitis, which occasionally destroys sufficient adrenal tissue to produce clinical adrenal insufficiency. Therapy for severe CMV infections includes intravenous ganciclovir, foscarnet, or cidofovir.

Mycobacterium avium-intracellulare complex (MAC) is one of the most frequent opportunistic infections occurring in patients with very low CD4 counts. The most frequent presentations are disseminated infection with persistent fevers, weight loss, and constitutional symptoms, as well as GI symptoms such as abdominal pain or chronic watery diarrhea. It often is diagnosed by obtaining a mycobacterial blood culture. Treatment with clarithromycin and ethambutol and rifabutin is required for weeks in an attempt to clear the bacteremia.

Because of the frequency and severity of common opportunistic infections, antimicrobial prophylaxis is routinely given as a patient's immune status declines. With CD4 counts <200/mm\ PCP prophylaxis should be given as one double-strength tablet of TMP-SMX three times per week. When counts fall to < 100/mm3 and patients have a positive toxoplasma serology, toxoplasmosis can be prevented by increasing to daily dosing of TMP-SMX. If CD4 levels are <50/mm3, MAC prophylaxis consists of clarithromycin 500 mg daily or azithromycin 1200 mg weekly. Prophylaxis can be discontinued if HAART is started and the patient's CD4 levels recover.

HAART includes a combination at least three drugs consisting of a "base" of a nonnucleoside analog reverse transcriptase inhibitor or a protease inhibitor along with a "backbone" of two nucleoside analog reverse transcriptase inhibitors. HAART is very potent and has dramatically revolutionized the treatment of HIV patients, producing suppression of viral replication and allowing a patient's CD4 count to recover. However, initiation of HAART likely is not practical in acutely ill patients because the medications are not easy to take and often cause side effects that can be confused with the underlying disease process. Additionally, within 1-2 weeks of starting HAART. improvement in the immune system can actually cause worsening symptoms as a result of host responses, termed the "immune reconstitution syndrome." Therefore, it is better to wait until the acute illness has resolved and to initiate antiretroviral therapy after the patient has recovered, in consultation with an infectious diseases expert, when reliable follow-up has been assured.

Comprehension Questions

[7.1 ] A 32-year-old woman with a 5-year history of HIV infection is noted to have a CD4 count of 100 cells/mm3. She is admitted to the hospital with a 2-week history of fever, shortness of breath, and a dry cough. Which of the following diagnostic tests would most likely confirm the diagnosis?

A. Silver stain of the sputum

B. Gram stain of the sputum showing gram-positive diplococci

C. Acid-fast smear of the sputum

D. Serum cryptococcal antigen

|"7.2] Which of the following is the most likely organism to cause pneumonia in a patient with AIDS?

A. Pneumocystis carinii

B. Mycobacterium tuberculosis

C. Histoplasmosis capsulation

D. Streptococcus pneumoniae f7.31 A 44-year-old woman infected with HIV is noted to have a CD4 count of 180 cells/mm'. Which of the following is recommended as a useful prophylactic agent in this patient at this point?

A. Fluconazole

B. Azithromycin

C. Trimethoprim-sulfamethoxazole

D. Ganciclovir

17.4] A 36-year-old woman with HIV is admitted with new-onset seizures. CT scan of the head reveals multiple ring enhancing lesions of the brain. Which of the following is the best therapy for the likely condition?

A. Rifampin, isoniazid, ethambutol

B. Ganciclovir

C. Penicillin

D. Sulfadiazine with pyrimethamine

Answers

[7.11 A. This clinical history is consistent with PCP. which is diagnosed by silver stain of the sputum, which often requires bronchoalveolar lavage to obtain.

17.21 1). The same organisms that cause community-acquired pneumonia in immunocompetent individuals are causative in HIV patients. Additionally. HIV patients are susceptible to other opportunistic infections. such as Pneumocystis.

17.3] C. When the CD4 count falls to <200 cells/mm3, trimethoprim-sulfamethoxazole (Bactrim) prophylaxis is generally initiated to prevent PCP. Prophylaxis against Mycobacterium avium-intracellulare complex usually is started when the CD4 count is <50 cells/mm3, and toxoplasmosis prophylaxis usually is started when the CD4 count is <100 cells/mm3.

|7.4| I). The most common cause of a mass lesion of the brain in an HIV patient is toxoplasmosis, which is treated with sulfadiazine with pyrimethamine.

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