Unusual Case of Pneumocystis jiroveci Pneumonia During Primary HIV Infection

Approximately 50% to 90% of patients with primary HIV infection have symptomatic illness.^1,2 The protean manifestations of this illness include fever, fatigue, myalgia, lymphadenopathy, and rash.^3,4 The vast majority (66% to 94%) of patients seek medical attention,^1,2 and 13% to 42% require hospitalization.^2,5 Although most patients have a self-limited illness of 14 to 21 days,^1,4-6 some have prolonged symptoms that may last up to 3 months and are considerably more severe. Symptoms lasting more than 14 days have been reported to be associated with faster progression to AIDS.⁷ Although rare, AIDS-defining illnesses occur during primary infection as a result of the severe immunosuppression that accompanies this syndrome.⁸

Scattered reports of severe and unusual manifestations involving every organ system, including renal⁹ and liver failure,¹⁰ neurological dysfunction,^11-15 and cardiac disease,¹⁶ have been reported in the setting of primary HIV infection. Few cases of opportunistic infections occurring concurrently with primary HIV infection can be found in the literature (Table 1).^17-24 We describe an unusual case of Pneumocystis jiroveci pneumonia (PCP) that occurred during a prolonged primary HIV infection.

CASE SUMMARY
A 39-year-old African American man was referred for the evaluation of newly diagnosed HIV infection and probable primary HIV infection. Approximately 2 weeks before presentation, he was evaluated for night sweats, diarrhea, anorexia, and a documented 20-lb weight loss over 2 to 3 weeks. He also reported a transient rash early in his illness. The patient had been well until the onset of these symptoms.

The results of enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were positive for HIV at that time. Negative HIV test results had been documented 1.5 years previously. In addition, there was documentation of negative results for HIV serological tests done on a yearly basis during the preceding 5 years. On presenting to the clinic 1 week after being informed of a reactive HIV serology, the patient had new complaints of fever, nonproductive cough, and progressive dyspnea of 1 week’s duration while his night sweats and diarrhea had not abated.

His medical history was significant for giardiasis and allergic rhinitis. There was no history of injection drug use, prior sexually transmitted diseases (STDs), or blood transfusions. The patient reported several unprotected heterosexual exposures over the preceding 3 months. The results of screening for concurrent STDs were negative at the time of presentation.

Physical examination findings were significant for a temperature of 40.3°C (104.6°F) and tachycardia. His respiration rate was 20 breaths per minute and oxygen saturation on pulse oximetry was 87% on room air. The patient was thin and appeared to be ill and in mild respiratory distress with conversational dyspnea. Oral candidiasis was present. Lung ausculatory findings were abnormal, with decreased breath sounds at bilateral lung bases with few crackles.

An arterial blood gas analysis showed a pH of 7.506 (normal, 7.35 to 7.45), PaCO₂ of 27 mm Hg (normal, 35 to 45), PaO₂ of 63 mm Hg (normal, 75 to 100), and oxygen saturation of 90% with an alveolar-arterial gradient of 53 mm Hg (normal [expected], 10 to 11). Laboratory test results were significant for anemia (hemoglobin level, 11.7 g/dL [normal, 14 to 18]), an elevated lactate dehydrogenase level (555 U/L [normal, 100 to 255]), and a serum creatinine level of 1.4 mg/dL (normal, 0.6 to 1.2). Liver enzyme levels were elevated, with an alanine aminotransferase level of 62 U/L (normal, 4 to 36) and an aspartate aminotransferase level of 108 U/L (normal, 8 to 33). A chest radiograph showed bilateral, patchy, interstitial infiltrates.

The patient was admitted directly to the ICU where treatment with intravenous ceftriaxone, azithromycin, and trimethoprim/sulfamethoxazole (TMP/SMX) was initiated. Prednisone was also begun to empirically treat PCP. Bronchoscopic evaluation with bronchoalveolar lavage revealed a positive direct fluorescence antibody to P jiroveci. Acid-fast bacilli stains were negative.

The patient’s respiratory status improved, and he was discharged on a regimen of oral prednisone and TMP/SMX. A repeated ELISA and Western blot analysis during hospitalization approximately 3 weeks after the initial positive test result showed a significant interval development of Western blot banding, indicating that the patient's presentation was likely a result of primary HIV infection (Table 2). Later during the hospitalization, his CD4⁺ cell count was 65/µL (6%), with an increased CD8⁺ cell count of 774/µL (70%) and a CD4/CD8 cell count ratio of 0.09. His HIV RNA level was 400,000 copies/mL.

Four weeks later, antiretroviral therapy was initiated with efavirenz, emtricitabine, and tenofovir. Genotyping, performed before the initiation of antiretroviral therapy, revealed HIV subtype B without evidence of drug resistance. The institution of antiretroviral therapy was delayed until after the treatment of acute PCP to minimize the risk of immune reconstitution syndrome while treating an acute opportunistic infection. Three weeks after initiation of antiretroviral therapy, the patient’s CD4⁺ cell count was 295/µL (15%) and his HIV RNA level was 849 copies/mL. On follow-up 3 months later, his CD4⁺ cell count was 278/µL (22%), and his HIV RNA level was now undetectable (less than 50 copies/mL).

DISCUSSION
The nonspecific nature of the common manifestations of primary HIV infection presents a major challenge to the clinician. Patients can usually describe an illness that precedes or coincides with seropositivity. The incidence is not affected by sex, age, or the mode of transmission.² In 12 patients with a single reported exposure, the median time to onset of symptoms from exposure was 15 days, with range of 5 to 29 days.¹ The symptoms associated with primary HIV infection typically last 2 to 3 weeks, but symptoms can last for 10 weeks or more.^1,6 Furthermore, there is evidence that seeking health care evaluation for symptoms²⁵ or a duration of symptoms of more than 14 days⁷ is associated with a more rapid decline in the CD4⁺ cell count.

Cooper and colleagues²⁶ first described the acute retroviral syndrome in 1985 as a “mono-like” illness. Since then, various studies have evaluated patients during and after primary HIV infection and have reported that the most common symptoms are fever, lymphadenopathy, fatigue, weight loss, diarrhea, rash, myalgia, pharyngitis, and oral or genital ulcerations.^1,4,27 Weight loss, a predominant symptom in our patient, is common,^2,28 with one study reporting its occurrence in 46% of patients with primary HIV infection.²

Because the signs and symptoms are nonspecific, primary HIV infection is frequently confused with other infectious diseases, such as secondary syphilis, infectious mono-nucleosis, viral hepatitis, and other viral illnesses. Even when there is a high index of suspicion, the appropriate diagnosis is frequently missed by clinicians.^1,6

In addition to the more common clinical findings described above, on occasion there are unusual presentations of primary HIV infection. As a group, neurological manifestations, including meningitis, meningoencephalitis,¹¹ acute disseminated encephalomyelitis,^12,13 and others,^14,15 appear to be the most frequently reported. In addition, acute renal failure,⁹ acute liver failure,¹⁰ and myopericarditis¹⁶ have been reported. Cases of rhabdomyolysis,²⁹ pancreatitis,³⁰ lymphocytic alveolitis,³¹ ulcerative esophagitis,³² and splenic rupture³³ have also been described.

The severe immunosuppression that can accompany primary HIV infection may also predispose patients to illnesses that are more often associated with late-stage HIV infection or are considered to be AIDS defining. Several case reports have shown that esophageal candidiasis can occur during primary HIV infection, but there have been few case reports of cytomegalovirus infections²³ or fatal disseminated toxoplasmosis.²⁴P jiroveci pneumonia occurring during primary HIV infection, as described in our patient, has been previously reported.^18,19

In 1993, notably before the HAART era and the availability of measuring HIV RNA levels, Vento and colleagues¹⁸ published a case series describing 3 patients with PCP that occurred during primary HIV infection. As in our case, all 3 patients experienced profound immunosuppression as a result of primary HIV infection, with depressed CD4⁺ cell counts ranging from 62/µL to 91/µL, predisposing them to infection with P jiroveci. In all cases, CD4⁺ cell counts returned to normal (300/µL to 400/µL) within 4 months of the onset of symptoms, demonstrating that profound CD4 lymphocytopenias can revert to normal after primary HIV infection without antiretroviral therapy. This finding supports the premise that a transient profound immunosuppression had occurred, leading to susceptibility to P jiroveci infection, rather than that the patient’s disease had progressed to AIDS.

While initial HIV serological test results were negative in these patients, all had reactive Western blot banding while being treated for pneumonia. Our case suggests that our patient presented later in the course of his primary HIV infection, since his Western blot banding developed over weeks. In addition, our patient’s HIV RNA level was 406,000 copies/mL, consistent with primary seroconversion. While HIV RNA testing was not available when Vento and colleagues¹⁸ reported their cases, the high p24 antigenemia described would likely serve as a surrogate.

While the exact mechanism is unknown, some postulate that the symptoms associated with primary HIV infection are a manifestation of the immune response to and/or the direct cytopathic effects of the virus and that the symptoms usually resolve as the HIV RNA level declines.^6,34-36 HIV RNA testing may detect HIV infection 1 to 3 weeks earlier than standard serological tests.^6,7,35 Serological tests for HIV may not be reactive during early phases of infection. However, investigators report that an early antibody response to 1 or 2 HIV antigens is often seen within 2 weeks after the onset of symptoms in primary HIV infection, when the blood antigen level is high.^35,37-40

The appearance of strong antibody responses to env (gp160, gp120) and gag (p24) proteins, the major viral core proteins, usually occurs earliest as the first possible detection of an antibody response in primary HIV infection, with some reports of this occurring as soon as 10 to 20 days after the onset of symptoms.^35-40 Core precursor proteins, such as p55 and core protein p15/17, usually follow.^36,37,39 Generally, serological tests are positive approximately 30 to 60 days after or during primary HIV infection.^6,35-37 A detectable HIV RNA level and evolving results of Western blot analysis are common diagnostic markers for primary HIV infection.³⁶ A less sensitive (“detuned”) ELISA test can be used to identify recent seroconversion. Results of the detuned assay generally become positive a mean of 129 days after infection. A nonreactive test suggests infection in the past 18 weeks.^36,41

Further evidence that our patient’s presentation was more likely secondary to primary HIV infection, as opposed to rapid progression to AIDS, is that the patient had had 4 documented negative results on routine HIV screening done on a yearly basis over the preceding 5 years. It is very unlikely that he experienced a primary HIV infection and that the disease progressed to AIDS in 1.5 years. This is further supported by the Collaborative Group on AIDS Incubation and HIV Survival, which published data on more than 13,000 patients before the widespread use of highly active antiretroviral therapy; the estimated risk of developing AIDS in 2 years was 2%.⁴²

In addition, our patient denied illness before the development of his presenting symptoms and reported a significant exposure with recent unprotected sexual encounters. The serial Western blot testing 3 weeks apart that demonstrated the development of more intense and new banding, including p24, is suggestive of a prolonged seroconversion, which has been previously described.^37,38,43 The prolonged (weeks) and severe nature of our patient’s primary HIV infection allowed time for the further development of antibody.

The advantages of initiating antiretroviral therapy during primary HIV infection continues to be debated because of a paucity of data from controlled clinical trials.³⁶ One of the theoretical benefits of the early use of antiretroviral therapy includes a unique opportunity during primary HIV infection for early modulation of the host’s immune response. Preliminary data indicate that treatment of primary HIV infection has a beneficial effect on laboratory markers of disease progression. Other treatment benefits that have been proposed include the mitigation of acute retroviral symptoms, preservation of cellular immune response, decreasing the initial viral load set point, limiting viral evolution and diversity, and reducing the risk of transmission at a time of extraordinarily high HIV RNA levels.

Disadvantages of the early use of antiretroviral therapy include toxicities associated with antiretroviral therapy, poorly defined long-term clinical benefits, the risk of developing drug resistance, and negative impact on quality of life.⁴⁴ Trials are ongoing to assess the long-term benefits of antiretroviral therapy during primary HIV infection,^36,44 and, currently, treatment during primary HIV infection is considered optional, but reasonable, within 6 months of HIV seroconversion.⁴⁴

Delay in the initiation of antiretroviral therapy in our patient until completion of treatment for acute PCP was, in part, because of the concern that immune reconstitution syndrome would develop while he was being treated for acute severe PCP. There is no consensus on optimal timing for the initiation of antiretroviral therapy in the setting of acute opportunistic infection. It may be difficult to distinguish between immune reconstitution syndrome and treatment failure for an opportunistic infection. Previously, studies have shown that initiating antiretroviral therapy within 30 days of treatment for opportunistic infection carries a 2-fold increase in risk of an immune reconstitution syndrome, although there was no difference in mortality.⁴⁵

Recently, results from a randomized multicenter strategy trial evaluating immediate versus deferred antiretroviral therapy in the setting of acute opportunistic infection showed that immediate antiretroviral therapy reduced death and AIDS progression over 48 weeks, but there was no significant difference in clinical or virological response between the immediate and delayed treatment arms. In this study, the median time between the initiation of treatment for an opportunistic infection and the start of antiretroviral therapy was 12 and 45 days in the immediate and deferred treatment arms, respectively. Patients with tuberculosis were excluded. There was no significant difference in the occurrence of immune reconstitution syndrome (8 immediate vs 12 deferred). These results suggest that consideration should be given to the early use of antiretroviral therapy in the setting of acute opportunistic infection.⁴⁶

CONCLUSION
Primary HIV infection can cause a wide spectrum of illness that ranges from mild disease to a severe and prolonged debilitating illness. The challenge for the clinician is the nonspecific nature of the symptoms that can result in misdiagnosis or unrecognizable HIV infection, delaying diagnosis. Our case underscores that primary HIV infection can produce a profound immunosuppression through CD4 lymphocytopenia, rendering the patient susceptible to an opportunistic infection. In the pre-HAART era, others have clearly shown that primary HIV infection is a transient immunosuppression that can predispose to opportunistic infection during this period of vulnerability rather than representing a manifestation of rapid disease progression to AIDS. While most cases of primary HIV infection are diagnosed by the detection of HIV RNA, the presence of HIV antibody can be found in this setting the longer the primary HIV illness lasts.

No potential conflict of interest relevant to this article was reported by the authors.

References:

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