Septic Shock Due to Toxoplasmosis in Patients Infected With the Human Immunodeficiency Virus

Septic Shock Due to Toxoplasmosis in Patients Infected With the Human Immunodeficiency Virus* ]ean-Christophe Lucet, M.D.; Marie-Pierre Bailly, M.D.;t Jean-Pierre Bedos, M.D.; Michel Wolff, M .D.; Bertrand Gachot, M.D.; and Fra~ois Vachon, M.D.

Purpolle: To describe the presentation and clinical course of septic shock due to lbwpltuma gondii in patients infected with the human immunodeficiency virus (HIV). lbtienta and methoda: From April 1988 to February 1992, nine HIV-infected patients were admitted because of predominant septic shock (7 patients) or developed septic shock in the ICU (2 patients). The recent CD4 + cell count ranged from 2 to 84 x 10"/L. Ruulta: The main clinical features were (1) a history of fever for longer than 15 days, with a recent increase to more than 39.5°C; (2) a recent history of dyspnea (<15 days, 8 cases; <7 days, 3 cases); and (3) recent onset of thrombocytopenia (6 of 9 cases). All patients were in shock (hyperkinetic pro61e in 6 of 7; hypokinetic in 1 of 7), and 8 of9 were in respiratory distress (ratio ofPaO, over fractional concentration of oxygen in the inspired gas of 117 ± 23; range, 88 to 155). Chest roentgenograms revealed diffuse alveolar infiltrates in six of nine cases. The serum lactate dehydrogenase (LDH) activity was 6,510 ± 5,080 IU/L

encephalitis is the most common T neurologic gondii disease in patients infected by the oxoplasma

human immunodeficiency virus (HIV).1.2 It is more frequent in Europe than in North America, possibly because of differences in dietary habits. 1 Extraneurologic forms of toxoplasmosis are rare in this setting and generally involve the lungs. 3-5 We observed 9 cases of disseminated toxoplasmosis with septic shock in HIV-infected patients over a 4-year period and herein report the history, presentation, clinical and laboratory findings, and outcome. MATERIALS AND METHODS

Between April 1988 and February 1992, there were 515 HIVinfected patients admitted to the ICU of the Bichat-Claude Bernard Hospital, Paris, France. Eighty-six had a diagnosis of isolated toxoplasmic encephalitis. Nine had a diagnosis of shock" due to disseminated toxoplasmosis, with or without the adult respiratory distress syndrome (ARDS).7 One of these cases has been reported elsewhere.• Septic shock was defined according to recent criteria as follows: sepsis-induced hypotension, with systolic blood pressure lower than *From the Intensive Care Unit, Department oflnfectious Disease, Bichat-Claude Bernard Hospital, Paris, France. tCurrently at Hopital de Ia Croix Rousse, Lyon, France. Manuscript received October 30, 1992; revision accepted February 17, 1993. Reprint requests: Dr. V.Vlff, S111'1Jiu de Reanimation Mallnfectieuses, HopUal Blchat-Claude Bernard, 75877 .fbris Cede.t 18, France

1054

(range, 1,010 to 15,450 lUlL). Serologic tests for T gondii were negative in two cases. To:wpltuma gondii was isolated from lung (9/9), bone marrow (517), or blood (212). One, 3, and 2 patients had brain, ocular, and myocardial involvement, respectively. No other microbial pathogens were isolated. Seven patients died, 5 less than 3 days after admission. Concluaion: Disseminated toxoplasmosis can cause septic shock in HIV-infected patients. In two cases, the disease was probably a primary infection. The association of high fever, acute dyspnea, recent onset of thrombocytopenia, and a very high level of LDH activity is suggestive of disseminated toxoplasmosis. (C~st 1993; 104:1054-58)

ARDS =adult respiratory distress syndrome; EUSA =enzymelinked immunosorbent assay; LDH =lactate dehydrogenase; MCC = May-Criinwald-Giemsa stain; PCP= Pneumocy.ti8 carinii pneumonia

90 mm Hg despite adequate Huid resuscitation, along with the presence ofhypoperfusion abnormalities or organ dysfunction.• The ARDS corresponded to severe lung injury, evaluated with the following three components: extent of roentgenographic densities; gas exchange abnormalities; and value of positive end-expiratory pressure.7 Toxoplasmosis was diagnosed by the detection of free trophozoites in the bronchoalveolar lavage (BAL) or bone marrow aspirate by direct examination with May-Griinwald-Giemsa (MGG) staining.•·• 1b:roplasma gondii was also detected in the blood by monocyte culture. 10•11 Specific IgG and lgM antibodies were detected by means of an enzyme-linked immunoabsorbent assay (ELISA) method, with a cutoff of 10 IU/L. Samples with negative results in the EUSA were further examined in the Sabin-Feldman dye test and by means of a sensitive agglutination assay." The following parameters were noted: risk factors for HIV infection; HIV-related opportunistic infections and malignant neoplasms; ongoing treatment at admission; clinical and laboratory findings; hemodynamic parameters; respiratory status; and outcome. The results are given as means± SD. REsuLTS

History

The nine patients (Table 1) comprised five homosexual men and four women, in whom the risk factors were drug abuse in three and unidentified in one. Eight of the 9 patients had AIDS at the time of the diagnosis of toxoplasmosis, and the mean absolute CD4 + cell count was 29 ± 28 X 1()6/L. Eight patients Septic Shock Due to Toxoplasmosis in AIDS Patients (L.ucet et sf)

Table 1-History of HIV-infected Patients With Septic Siwek due to Tcnoplasmosis Previous HIV-related Opportunistic Infection or Malignancy

Patient, Sex, Age (yr)

AIDS Risk Croup

l,F,27 2,M,35

Drug addict Homosexual

Tuberculosis Kaposi's sarcoma

3,M,51

Homosexual

Esophageal candidiasis; Kaposi's sarcoma

4,F,27 5,F,23 6,M,35 7,M,64

Drug addict Drug addict Homosexual Homosexual

PCP PCP

8,F,37

Unknown

9,M,32

Homosexual

Cryptosporidiosis; PCP Esophageal candidiasis; tuberculosis; Salmonella septicemia; Kaposi's sarcoma Tuberculosis; cryptococcosis None

CD4+ cells X 10"/L*

Tgondii Antibodies (IgC/IgM)t

84 5

27410 1,00010

2

4410

51 7

010 50010 2010

8

30010

19

010

Inhaled pentamidine

34

010

Zidovudine; inhaled pentamidine

Current Therapy Zidovudine Zidovudine; inhaled pentamidine Zidovudine; inhaled pentamidine Inhaled pentamidine Sulfamethoxazole-trimethoprim Inhaled pentamidine None

*Flow cytometry. tELISA.

had previously developed an opportunistic infection or malignant neoplasm. Seven patients were receiving prophylactic therapy against Pneumocystis carinii pneumonia (PCP), and four were receiving zidovudine. None was receiving anti- Toxoplasma prophylaxis. Six patients had serologic markers of prior T gondii

infection; the other three had negative serologic tests on admission or during the month prior to admission and also several months previously (7, 14, and 18 months). Two of these three patients also had negative results on the Sabin-Feldman dye test and the sensitive agglutination assay.

Table 2-Clinical Data, Diagnostic Procedures, and Outcome in HIV-infected Patients with Septic Siwek due to Tcnoplasmosis

Case

2

3 4

5 6 7 8

9

Presentation (Length, days) Fever; dyspnea and cough (15); thrombocytopenia (30) Fever (60); dyspnea and cough (3); thrombocytopenia (21) Fever (30); dyspnea and cough (2); thrombocytopenia (7) Fever (15); dyspnea and cough (10); thrombocytopenia (7) Fever (15); dyspnea and cough (10) Fever (25); dyspnea and cough (14) Fever (7); dyspnea and cough (10) Dyspnea and cough (2); thrombocytopenia (4) Fever (45); thrombocytopenia (3)

Fever on Admission,

Infiltrates Hemodynamic on Chest Profile (CII Platelets X-ray Film PAWP/SVRI)* X 10"/L

WBCs (PMNs) X 10'/Lt

40

Diffuse alveolar

5.4/12/640

13

2.2 (1.8)

40

Diffuse alveolar

7.31201960

15

2.2 (1.3) 12,650 Lung; bone marrow; brain

40

Diffuse alveolar

40.4

Diffuse alveolar

1.7/201720

32

39.7

Bibasilar alveolar Interstitial

5.l/9/720

60

•c

40.2 39.7 40.2

39.8

Diffuse alveolar Diffuse alveolar Bibasilar alveolar

12

7.514/1,120

139

Serum LDH, lUlL

Sites*

6,425 Lung; bone marrow

0.5 (0.4) 15,450 Lung; bone marrow, liver (PM) 10.3 (9.1) Lung(PM); heart (PM); liver(PM) 3.9 (3.5) Lung; hearts, eye 4.5 (4.0) 3,160 Lung

150

1.9 (1.5)

1,010 Lung

6.31101480

35

4.9 (4.6)

4.31011' 120

10

2.9 (2.2)

2,340 Lung; eye; bone marrow; blood 4,510 Lung; bone marrow; eye; blood

Outcome (Day of Death) Died (d 2) Died (d3) Died (d 1) Died (d 1) Cured Cured Died (d 2) Died (d 7) Died (d 7)

*CI, Cardiac index in liters per minute per square meter; PAWP, pulmonary artery wedge pressure in millimeters of mercury; and SVRI, systemic vascular resistance index in dynes·seconds per em• per square meter. tPMN , Polymorphonuclear cells. *PM , Post mortem . CHEST I 104 I 4 I OC'IOBER, 1993

1055

Presentation The patients had been febrile (38° to 39°C) for 7 to 60 days, and 8 had had respiratory signs for 2 to 15 days prior to admission (Table 2). The body temperature had exceeded 39. 7°C in every case for a few days immediately prior to admission. Six patients had a history (3 to 30 days) of recent thrombocytopenia. The chest roentgenograms obtained a few days before admission were normal in four cases and showed signs of interstitial pneumonia in five cases (associated with hyperdense nodules in one). The reasons for admission to the ICU were shock (according to the recent definition6 ) in seven cases, which was associated with respiratory distress in six cases and neurologic disturbances in one case (case 2). Two patients (patients 5 and 7) were admitted because of pneumonia and developed shock after admission (days 8 and 3, respectively). The mean simplified acute physiology score (SAPS) on admission was high, at 17.2 ± 4.5. 13 Insertion of a Swan-Ganz catheter was carried out during the shock phase in seven cases and revealed a hyperkinetic profile in six cases (cardiac index, 6.0± 1.3 Uminlm 2 ; pulmonary artery wedge pressure, 9.2 ± 6.3 mm Hg; systemic vascular resistance index, 840 ± 248 dyne·s/cm 5 ·m2 ) . The profile was hypokinetic in patient 4, in whom diffuse myocarditis with T gondii cysts was found at autopsy. All of the patients received initial Ouid resuscitation and secondary inotropic drugs (dopamine in 9; epinephrine in 6; and dobutamine in 1) within the first 24 h of shock. Seven patients had respiratory distress on admission and were immediately placed on mechanical ventilation, while patients 2 and 5 were intubated on days 2 and 8, respectively. The ratio of Pa0 2 over the fractional concentration of oxygen in the inspired gas (Fio2) was less than 175 in eight patients (117 ± 23), and seven patients required PEEP above 5 em H 20. Six patients had diffuse alveolar infiltrates, while two (patients 5 and 9) had bibasilar alveolar consolidation. Finally, eight patients fulfilled the criteria of ARDS. 7 Patient 6 had a Pa0/Fio2 ratio of 250 and did not require PEEP; the chest roentgenogram showed diffuse interstitial infiltration. The laboratory findings were relatively uniform. Seven patients had thrombocytopenia (<60x 106/L), which was associated with a recent neutropenia on admission in one (case 3) and with secondary neutropenia in another (case 9). The serum lactate dehydrogenase (LDH) activity was very elevated in the seven patients tested (6,510±5,080 lUlL; normal value, <450 lUlL). Hepatic enzyme activities were also elevated, with a stronger increase in aspartate aminotransferase (528 ± 424 lUlL; range, 13 to 1,290 IU/ L; normal value, <40 lUlL) than in alanine aminotransferase (140± 120 lUlL; range, 39 to 289 lUlL). 1056

The serum creatine kinase value was 1,520± 1,300 lUlL (range, 52 to 3,330 lUlL; normal value, <200 lUlL). Toxoplasmosis was diagnosed within 4 days of admission in 8 cases and at autopsy in 1. Toxoplasma gondii was isolated from the lung in every case, either by means ofBAL (n = 7), by open-lung biopsy following normal results of BAL (n = 1), or at autopsy (n = 1). Toxoplasma gondii was also recovered from the bone marrow in five of the seven patients tested (patients 1, 2, 3, 8, and 9). Signs of toxoplasmosis were found during ocular fundus examination in 3 cases (cases 5, 8, and 9); the ocular disease cleared after specific treatment in case 5. Cranial computed tomography (CT) was performed in five cases shortly before or after admission to the ICU and showed evocative signs of toxoplasmosis in one case (case 2). Blood cultures performed in cases 8 and 9 before starting specific therapy both yielded T gondii, and cultures thereafter showed a gradual fall in the number of circulating parasites during treatment. Infestation of the liver was detected postmortem in two cases. Cardiac involvement was documented in one case (case 4) and was suspected in another case (case 5) on the basis of conduction disturbances which resolved during antiToxoplasma therapy. No other infections were documented, despite extensive examination of blood, BAL, and bone marrow samples. Two patients (patients 3 and 4) underwent an autopsy. Seven of the nine patients received anti-Toxoplasma therapy (pyrimethamine-clindamycin, 5; pyrimethamine-sulfadiazine, 2). Seven patients died, 5 in less than 3 days. The cause of death was hemodynamic with multiorgan failure in five cases and secondary neurologic failure in two (patients 8 and 9). Two patients were cured, one with pyrimethamine-sulfadiazine and one with pyrimethamine-clindamycin. DISCUSSION

Toxoplasmosis related to HIV infection is more frequent in Europe than in the United States, probably due to different dietary habits and, therefore, a different seroprevalence in the general population. 1 Extraneurologic toxoplasmosis is rare. 3 Two large series of patients with AIDS found extraneurologic sites in 3 percent of the cases post mortem, while cerebral toxoplasmosis was found in 9 and 35 percent of the cases. 14 •15 Another prospective publication reports a prevalence of 7/169 (4 percent) positive for T gondii in the BAL of HIV-positive patients. 16 The incidence of extraneurologic toxoplasmosis appears to have been on the increase in recent years. In a recent study of 13 patients with pulmonary toxoplasmosis, the incidence of PCP and pulmonary toxoplasmosis over a 4-year period in 3 Parisian hospitals was reported. 5 The toxoplasmosis/pneumocystosis ratio Septic Shock Due to Toxoplasmosis in AIDS Patients (Lucet et at)

went from 1/300 to 1/40 between 1984 to 1986 and 1988. There are two possible reasons for this apparent increase. First, the survival of patients with AIDS is increasing with better management of opportunistic infections, the use of pentamidine as primary and secondary anti-PCP prophylaxis, and the availability of zidovudine . Disseminated toxoplasmosis generally occurs in patients with a CD4 + cell count below than 100 X 1()6/L, and the number of such patients will probably increase in the coming years. Secondly, contrary to P carinii, T gondii is present in small numbers in pathologic specimens, and its identification by means of M GG staining can be difficult. Extraneurologic toxoplasmosis is a recent discovery in patients with AIDS, and its diagnosis could have been previously missed. 9 Nevertheless, this disease is still rare, even in France. Septic shock due to toxoplasmosis was 10 times less frequent than of toxoplasmic encephalitis observed during the same period and represented 2 of the 11 cases of septic shock in HIV-infected patients seen in 1992. The incidence of toxoplasmosis may fall in the coming years. Six of our patients received pentamidine as prophylaxis for PCP, and only one received trimethoprim-sulfamethoxazole, a combination shown to prevent Toxoplasmic encephalitis in a recent retrospective study. 17 The trimethoprim-sulfamethoxazole combination is now recommended as first-line prophylaxis for PCP, 18 and its increasing use could prevent the onset ofT gondii infections. It can be difficult to determine the precise onset of signs attributable to toxoplasmosis, given the multiple potential causes of fever in these patients; however, the clinical presentation is homogeneous: most patients had a several-week history of fever, and the temperature increased to above 39.5°C a few days before admission to intensive care. Respiratory signs are frequent and far more acute than in PCP, with onset a few days before admission. Achest roentgenogram obtained a few days prior to admission was normal in half of the patients in this series and only showed "typical" signs of toxoplasmosis in one case (diffuse interstitial infiltrate with nodular reinforcement of the two bases). 5 When BAL fails to yield P carinii and the course is acute, disseminated toxoplasmosis should be suspected, and measures should be taken to avoid the onset of shock. Hemodynamic parameters are those observed during septic shock, with an elevated cardiac index, low systemic vascular resistance , and low or normal filling pressure during treatment with inotropic drugs. In the case of patient 4, cardiac output was low due to specific involvement of the myocardium, but the shock was partly vasoplegic, with low systemic vascular resistance. Toxoplasma gondii was probably responsible for shock, on the basis of the involvement of several organs

(at least two organs in seven of the nine patients), the positive blood cultures in the two most recent cases, and the apparent absence of other pathogens. Shock was usually associated with ARDS, which was identical to that observed during bacterial septic shock, with diffuse, bilateral alveolar infiltrates in most cases. The occurrence of shock in the setting of disseminated toxoplasmosis is uncommon; no report of disseminated toxoplasmosis clearly points out shock, except for 2 cases out of a series of 13 with pneumonia in patients with AIDS. 5 Laboratory findings were similar in the nine patients. Serum LDH activity was elevated, more so than could be explained by possible increases in hepatic enzyme activity. As recently reported, the values were generally higher than those observed during severe PCP 19 and should, in conjunction with the respiratory signs, point to toxoplasmosis. Seven patients had thrombocytopenia on admission. The onset (or worsening) of thrombocytopenia was recent (<1 month) in six cases. There are several possible causes for thrombocytopenia in this setting, including bone marrow invasion, disseminated intravascular coagulation, and severe sepsis. Bone marrow involvement was probably responsible for the initial (n = 1) and secondary (n = 1) neutropenia in this series. Disseminated toxoplasmosis was always diagnosed rapidly in the ICU by means of BAL (7/8) or bone marrow sampling (517). It is likely that more aggressive management would have led to an earlier diagnosis of toxoplasmosis, prior to admission to the ICU. Only patient 2 had objective neurologic signs and CT findings evocative of cerebral toxoplasmosis. The CT scan was normal in the other four patients who underwent the examination. Nonetheless, the cause of death was secondarily neurologic in two cases (cases 8 and 9) and occurred when the shock was resolving. Although the CT scan was normal, diffuse encephalitic toxoplasmosis may have contributed to the neurologic deterioration in these two patients. Contrary to neurologic forms of toxoplasmosis, in which serologic tests are generally positive, 20 two of our patients had negative findings, even in sensitive assays. It is generally agreed that toxoplasmosis in HIV-infected patients involves reactivation of a latent infection due to the immunodeficiency. 1·20 The negative serologic results in the two patients in this study were not due to late seroreversion, as antibodies were not detectable several months before the onset of symptoms. This suggests that clinical toxoplasmosis resulted from a primary acquired infection with abnormal humoral response due to the profound immunodeficiency. 21 In this setting the pulmonary involvement may reflect the tropism of T gondii for the lung, as recently observed during the acute phase of infection in an experimental model. u CHEST I 104 I 4 I OClOBER, 1993

1057

In conclusion, T gondii can cause septic shock, which is generally associated with ARDS. Clinical signs are nonspecific, but laboratory findings are suggestive. The gravity of extraneurologic forms of toxoplasmosis and the simple detection of the parasite call for more aggressive management of these patients in order to avoid shock. The severity ofT gondii shock may warrant prophylactic treatment in endemic areas. ACKNOWLEDGMENTS: We thank Professor F. Derouin (Department of Parasitic Disease, Hopital Saint-Louis, Paris) for perfonning blood cultures and Dr. A. Motard (Department of Parasitic Disease, Hopital Bichat-Ciaude Bernard, Paris) and Dr. P. Tulliez (Toxoplasmosis Laboratory, Institut de Puericulture, Paris), for perfonning serologic tests. REFERENCES

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Septic Shock Due to Toxopla!moels In AIDS Patients (l.ucet et al)