Abstract
Histoplasmosis is among the main acquired immunodeficiency syndrome (AIDS)–defining conditions in endemic areas. Although histoplasmosis has a worldwide distribution, histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with human immunodeficiency virus (PLHIV) is rarely reported.
This study aimed to describe the incidence and features of histoplasmosis-associated IRIS in a cohort of PLHIV.
A retrospective multicenter study was conducted in French Guiana from 1 January 1997 to 30 September 2017. The target population was represented by PLHIV who presented an episode of histoplasmosis within 6 months after antiretroviral therapy initiation. We used a consensual IRIS case definition, submitted to the agreement of 2 experts. Each case was described using a standardized questionnaire, and all patients gave informed consent.
Twenty-two cases of histoplasmosis-associated IRIS were included (14 infectious/unmasking and 8 paradoxical), with an overall incidence rate of 0.74 cases per 1000 HIV-infected person-years (95% confidence interval, 0.43–1.05). Mean age was 40.5 years. The ratio of males to females was 1:4. Median time to IRIS was 11 days (interquartile range 7–40 days) after antiretroviral therapy initiation. The main clinical presentation was fever, without any specific pattern, and disseminated disease. We reported 2 severe cases and partial or complete recovery at 1 month was the rule. Twenty-two cases were identified in the literature with similar characteristics.
Histoplasmosis-associated IRIS incidence was low but generated significant morbidity in PLHIV. In endemic areas, screening for latent or subclinical histoplasmosis should be implemented before antiretroviral therapy initiation.
Histoplasma capsulatum is a dimorphic fungus that lives in soils contaminated with bird or bat droppings [1]. Infection occurs mainly through inhalation of spores from the soil [1]. Histoplasmosis is usually asymptomatic or mild and self-limiting in immunocompetent hosts [1]. Among immunosuppressed individuals, notably people living with human immunodeficiency virus (PLHIV), infection results mainly in a disseminated and lethal disease without treatment [1].
Histoplasma capsulatum has a worldwide distribution. High endemic regions are mainly described in the Americas. Human immunodeficiency virus (HIV)–associated histoplasmosis is the top acquired immunodeficiency syndrome (AIDS)–defining condition in French Guiana, but it is uncommon or neglected in other American countries [2].
The diagnosis of histoplasmosis is difficult because culture-based diagnostic methods are slow, poorly sensitive, and require medical mycology skills [3]. Histoplasma antigen-detection methods or molecular biology techniques performed in body fluids are either unavailable outside of the United States or not commercially available, respectively [3]. Furthermore, physicians’ awareness and diagnostic and treatment capacities are lacking, making histoplasmosis a neglected disease, notably in low- and middle-income countries with high endemicity [4].
Immune reconstitution inflammatory syndrome (IRIS) is an excessive inflammatory response against a pathogen, which sometimes occurs when the immune system is rapidly restored following antiretroviral therapy (ART) initiation [5, 6]. No test is currently available to confirm IRIS diagnosis. IRIS case definition relies on the context of a recent introduction of effective ART (HIV viral load decrease with or without CD4 count increase) together with a flare-up of an unknown or recently treated infection [5, 6].
Histoplasmosis-associated IRIS occurring in PLHIV has been infrequently reported in endemic areas [7, 8]. Little is known about its clinical spectrum and outcomes, and no incidence data are available.
This study aimed to describe the incidence, clinical presentation, treatment, and outcome of histoplasmosis-associated IRIS cases among PLHIV residing in an endemic area for H. capsulatum. A secondary objective was to compare cases with those published to date.
METHODS
Study Design
A retrospective multicenter study was conducted from 1 January 1997 to 30 September 2017 in the 3 main hospitals of French Guiana.
The study inclusion criteria were as follows: adult older than 18 years, confirmed HIV infection, confirmed histoplasmosis (culture and/or histopathology and/or DNA detection), and a histoplasmosis-associated IRIS episode within 6 months after ART initiation or resumption. Exclusion criteria were histoplasmosis and tuberculosis coinfection within 3 months around IRIS symptom onset, missing files or data, and nonadherent patients to antifungals and/or ART.
Case Definition
IRIS case definition followed the French PLHIV care and treatment guidelines [6]: (1) appearance of clinical manifestations after initiation of effective ART (>1-log decrease in plasma HIV viral load with or without a CD4 count increase), (2) an inflammatory and atypical clinical presentation, and (3) signs or symptoms unexplained by newly acquired infection, treatment failure of a previously identified opportunistic infection, adverse treatment effect, or other cause.
Cases were classified as paradoxical IRIS (flare-up of a previously treated histoplasmosis) or infectious/unmasking IRIS (flare-up of a latent asymptomatic or subclinical histoplasmosis).
It is noteworthy that, according to the clinical presentation of each patient upon hospital admission, all PLHIV included in the study were screened for any potential diagnosis, AIDS-related or not, including mycobacterial infections or fungal infections—for instance, following the French recommendations on PLHIV care and treatment [6].
Data Collection Procedures
First, we screened all PLHIV in the cohort with an episode of histoplasmosis within 6 months following ART initiation. Their medical files were reviewed and patients were included according to the study criteria. Sociodemographic data, care and treatment, and survival status at the latest contact date were collected using a standardized form. We considered the most recent CD4 count level and HIV viral load within 3 months before ART initiation, within 3 months around the IRIS diagnosis, and within 3 months around the first histoplasmosis episode for paradoxical IRIS only. In the absence of a consensual definition for severity, we considered IRIS cases admitted to an intensive care unit (ICU) as severe. Since the use of liposomal amphotericin B is recommended in severe HIV-associated histoplasmosis cases, we used it as a proxy to describe IRIS severity [9].
Second, the standardized forms of selected cases were reviewed by 2 experts. Following the experts’ consensual evaluation, IRIS cases were classified as follows: (1) certain, case definition fulfilled; (2) probable, relevant case with at least 1 case-definition criterion missing; and (3) non-IRIS, data missing or not sufficient to reach a conclusion.
All certain and probable IRIS cases were included in the study and further labeled as paradoxical or infectious/unmasking IRIS by experts.
Finally, cases were compared with those published to date (the literature review strategy is detailed in the Supplementary Material).
Ethics Statement
All patients were enrolled in the PLHIV cohort of French Guiana, part of the French Hospital Database for HIV, and approved by the Commission Nationale de l’Informatique et des Libertés on 27 November 1991 [10]. All patients signed an informed-consent form.
Statistical Analysis
Analyses were performed using Stata 13.0 (StataCorp). Incidence rates per 1000 HIV-infected person-years were computed together with a 95% confidence interval (CI). We tested trends in incidence rates over 3 relevant time periods using a Wilcoxon-type test for trend. Statistical significance was set at P < .05. Time periods were based on the evolution of the recommended CD4 count-level threshold to initiate ART in ART-naive PLHIV in France: less than 200 CD4 cells/μL (until 2004), less than 350 CD4 cells/μL (until 2012), and treat all PLHIV since 2013. For continuous variables, after graphic verification of normality, we calculated means (± standard deviation) or medians with 25–75% interquartile ranges. An increase in CD4 counts was considered significant if the CD4 count difference between ART initiation and the time of IRIS, was ≥25 cells/µL (Robertson’s criteria) [11].
RESULTS
A detailed description of histoplasmosis-associated IRIS cases observed in French Guiana and a comparison with cases reported in the literature are presented in Tables 1 and 2, respectively.
IRIS Selection, Incidence, and Trends
Among 265 cases listed in the PLHIV cohort, 22 IRIS cases (14 infectious/unmasking and 8 paradoxical) were finally included in the study: 12 certain and 10 probable (Figure 1).
Flowchart. Abbreviations: ART, antiretroviral therapy; IRIS, immune reconstitution inflammatory syndrome; PLHIV, people living with human immunodeficiency virus.
Between 1997 and 2017, the overall incidence rate of histoplasmosis-related IRIS was 0.74 cases per 1000 HIV-infected person-years (95% CI, 0.43–1.05). In each time period—1997–2004, 2005–2012, and 2013–2017—the numbers of IRIS cases observed were 5, 8, and 9, and incidence rates were 0.91 (0.11–1.71), 0.61 (0.19–1.04), and 0.82 (0.28–1.35) per 1000 HIV-infected person-years, respectively (P-trend = .48).
Baseline Characteristics
The mean age was 40.5 (±7.0) years and the ratio of males to females was 1:4 (13 men and 9 women). Seven patients originated from French Guiana, 4 from Suriname, 3 from Brazil, 3 from Haiti, 2 from mainland France, 1 from Guyana, 1 from Colombia, and origination was unknown for 1 patient.
Clinical Presentation, Care, and Treatment of 22 Cases of Histoplasmosis-associated Immune Reconstitution Inflammatory Syndrome: French Guiana, 1 January 1997 to 30 September 2007
| Pre-ART | ART Initiation | IRIS Associated With Histoplasma capsulatum | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case Number | Histoplasmosis Diagnosis | Time of Antifungals- ART (days) | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)a | ART Regimen | Time of ART- Symptoms Onset (days) | Clinical Presentation | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)b | Histoplasmosis Diagnosis | IRIS Type and Class | Management | Comments |
| 1 | Liver (histology) | 78 | 204;1737;>500 000(>5.7) | Lamivudine, didanosine, efavirenz | 19 | Fever, dyspnea, interstitial syndrome, abdominal pain, diarrhea | 196;528;527(2.7) | Not done | Paradoxical certain | ART+Itra continuation | … |
| 2 | Colon and Pulmonary (culture) | 27 | 24; NA; 480 014 (5.7) | Lamivudine, didanosine, efavirenz | NA | Fever, weight loss, diarrhea, hepatomegaly, anemia, acute renal failure | 511; 1282; 117 (2.0) | Not done | Paradoxical probable | ART+Itra continuation | CD4-CD8 counts and HIV viral load done day 56 from hospital admission for IRIS |
| 3 | Lymph node and bone marrow (culture) | 14 | 4.9; 59; 4 000 000 (6.6) | Tenofovir, emtricitabine, darunavir/r | 43 | Fever, papular rash, lymph node enlargement, abdominal pain, diarrhea, anemia, hyperferritinemia | 102; 356; 150 (2.2) | Lymph node (direct -, culture -) | Paradoxical certain | ART+Itra continuation | … |
| 4 | Pulmonary (PCR) | 27 | 15; 29; 271 462 (5.4) | Tenofovir, emtricitabine, efavirenz | 30 | Weight loss, lymph node enlargement, interstitial syndrome, anemia | 106; 854; 229 (2.3) | BAL (direct -, culture -) | Paradoxical certain | ART+Itra continuation, corticosteroids (2 weeks) | Pre-ART pneumocystis coinfection (ME and DFA and PCR) |
| 5 | Colon (culture and PCR) | 42 | 25; 513; 2 946 576 (6.4) | Tenofovir, emtricitabine, atazanavir/r | 11 | Fever, chest pain, ankle arthritis, abdominal pain, anemia | NA | Not done | Paradoxical probable | ART+Itra continuation | … |
| 6 | Colon (culture) | 0 | 48; 523; 37 000 (4.5) | Tenofovir, abacavir, atazanavir/r | 50 | Extensive ulcerative and hemorrhagic colitis | 6; 120; 47 (1.6) | Colon (direct, culture) | Paradoxical probable | ART continuation, Itra continuation then LAmb, Colectomy (day 55) | Cardiac arrest (day 55), CMV coinfection (PCR) |
| 7 | Blood (culture) | 12 | 11; 65; 400 000 (5.6) | Tenofovir, emtricitabine, atazanavir/r | 6 | Fever, abdominal pain, miliary nodules, lymph node enlargement, anemia | 32; 65; 19 953 (4.3) | Bone marrow (direct -, culture -) | Paradoxical certain | ART + Itra continuation | HIV viral load done day 94 from symptoms onset, 1 log after 6 months on ART |
| 8 | Lymph nodes (culture) | 155 | 272; 2727; 165 969 (5.2) | Tenofovir, emtricitabine, raltegravir | 59 | Lymph node enlargement, cough, hepatic cytolysis | 529; 2981; 947 (2.9) | Not done | Paradoxical certain | ART + Itra continuation | … |
| 9 | … | … | 95; 335; 367 502 (5.6) | Stavudine, didanosine, nevirapine | 38 | Wasting syndrome, colonic ulcers, pleural effusion, anemia | 211; 122; 63 (1.8) | Colon (histology) | Unmasking certain | ART continuation, LAmb (2 weeks), Itra | … |
| 10 | … | … | 323; 808; 68 771 (4.8) | Lamivudine, stavudine, indinavir | 7 | Lymph node enlargement, splenomegaly, papular rash, anemia | 320; 517; 29 859 (4.4) | Lymph nodes (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load <1 log on day 30 from symptoms onset and ART discontinued |
| 11 | … | … | 113; 828; 21 190 (4.3) | Lamivudine, zidovudine, indinavir | 7 | Fever, cough, interstitial syndrome, esophageal ulcers, anemia, hepatic cytolysis | 128; 760; 500 (2.7) | Liver (culture) | Unmasking probable | ART continuation, LAmb (8 days), Itra | CD4-CD8 counts and HIV viral load done day 80 from symptoms onset |
| 12 | … | … | 21; 1448; NA | Zalcitabine, zidovudine | NA | Fever, weight loss, l ymph node enlargement, cholestasis | 19; 478; NA (NA) | Lymph nodes (histology) | Unmasking probable | ART continuation Itra (7 days), LAmb (3 days), Itra, corticosteroids | … |
| 13 | … | … | 56; NA; 147 615 (5.2) | Tenofovir, lamivudiene, efavirenz | 100 | Fever, meningoencephalitis, interstitial syndrome, diarrhea, arthralgia, anemia | 93; 367; <20 (<1.3) | CSF and blood and bone marrow (culture) | Unmasking certain | ART continuation, LAmb (3 days), Itra | … |
| 14 | … | … | 179; 1260; 22 000 (4.3) | Tenofovir, emtricitabine, elvitegravir, cobicistat | 5 | Fever, cough, diarrhea, esophageal ulcer, lymph node enlargement, focal neurologic event, DIC, adrenal insufficiency | 238; 2640; 360 (2.5) | Lymph nodes a esophagus (histology) | Unmasking certain | Itra, LAmb, Itra. ART continuation (washout 7 days) | … |
| 15 | … | … | 392; 787; 61 586 (4.7) | Lamivudine, zidovudine, lopinavir/r | 11 | Abdominal pain, antepartum hemorrhage, anemia, premature birth | NA | Placenta (culture and PCR) | Unmasking probable | ART continuation, cesarean section (week 31), Itra | Itra started 27 days after cesarean section upon culture results in an asymptomatic patient |
| 16 | … | … | 10; 128; NA (NA) | Abacavir, lamivudine, atazanavir/r | 9 | Fever, cough, lymph node enlargement, hepatomegaly, splenomegaly | NA | Lymph nodes (histology) | Unmasking probable | ART discontinuation, LAmb (14 days), Itra | MAC coinfection (histology and culture) |
| 17 | … | … | 74; 440; 1500 (3.1) | Tenofovir, emtricitabine, atazanavir/r | 9 | Fever, dyspnea and cough, lymph node enlargement, bicytopenia | 56; 267; 340 (2.5) | Blood (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load ↓ <1 log ART stopped 1 week before blood check |
| 18 | … | … | 35; 190; 2 300 000 (6.3) | Tenofovir, emtricitabine, darunavir/r | 1 | Fever, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, splenomegaly, MAS | 65; 104; 530 (2.7) | Bone marrow and blood (culture) | Unmasking probable | ART continuation, LAmb (5 days), Itra | Probable pre-ART latent histoplasmosis undiagnosed |
| 19 | … | … | 80; 1273; 1 251 258 (6.1) | Tenofovir, emtricitabine, efavirenz | 6 | Fever, weight loss, dyspnea, focal neurologic event, anemia, hepatic cytolysis | 262; 2594; 360 (2.5) | Bone marrow (culture and PCR), blood and CSF (PCR) | Unmasking certain | ART continuation, Itra (6 days), Itra+LAmb (6 days), Itra (4 days), Fluco (Itra adverse event) | CD4-CD8 counts and HIV viral load done day 58 |
| 20 | … | … | 25; 277; 32 240 (4.5) | Abacavir, lamivudine, darunavir/r | 19 | Fever, small bowel perforation, peritonitis, interstitial syndrome, anemia | 25; 153; <20 (<1.3) | Blood (culture), small bowel (histology) | Unmasking certain | ART continuation, LAmb+Itra, corticosteroids (3 weeks), small bowel resection | Consecutive IRIS episodes: severe pneumonia (day 19), small bowel perforation with peritonitis (day 69) |
| 21 | … | … | 59; NA; 353 000 (5.5) | Tenofovir, emtricitabine, lopinavir/r | 50 | Lymph node enlargement, anemia | 249; NA; 697 (2.8) | Lymph nodes (histology) | Unmasking certain | ART discontinuation, Itra | MAC coinfection (AFB smear and PCR) |
| 22 | … | … | NA; NA; 1 100 000 (6.0) | Tenofovir, emtricitabine, efavirenz | 10 | Fever, dyspnea, cough, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, MAS | 139; 478; 11 159 (4.0) | Bone marrow (culture) | Unmasking certain | ART continuation, LAmb (8 days), Itra | Probable MAS: hemodiluted bone marrow |
| Pre-ART | ART Initiation | IRIS Associated With Histoplasma capsulatum | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case Number | Histoplasmosis Diagnosis | Time of Antifungals- ART (days) | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)a | ART Regimen | Time of ART- Symptoms Onset (days) | Clinical Presentation | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)b | Histoplasmosis Diagnosis | IRIS Type and Class | Management | Comments |
| 1 | Liver (histology) | 78 | 204;1737;>500 000(>5.7) | Lamivudine, didanosine, efavirenz | 19 | Fever, dyspnea, interstitial syndrome, abdominal pain, diarrhea | 196;528;527(2.7) | Not done | Paradoxical certain | ART+Itra continuation | … |
| 2 | Colon and Pulmonary (culture) | 27 | 24; NA; 480 014 (5.7) | Lamivudine, didanosine, efavirenz | NA | Fever, weight loss, diarrhea, hepatomegaly, anemia, acute renal failure | 511; 1282; 117 (2.0) | Not done | Paradoxical probable | ART+Itra continuation | CD4-CD8 counts and HIV viral load done day 56 from hospital admission for IRIS |
| 3 | Lymph node and bone marrow (culture) | 14 | 4.9; 59; 4 000 000 (6.6) | Tenofovir, emtricitabine, darunavir/r | 43 | Fever, papular rash, lymph node enlargement, abdominal pain, diarrhea, anemia, hyperferritinemia | 102; 356; 150 (2.2) | Lymph node (direct -, culture -) | Paradoxical certain | ART+Itra continuation | … |
| 4 | Pulmonary (PCR) | 27 | 15; 29; 271 462 (5.4) | Tenofovir, emtricitabine, efavirenz | 30 | Weight loss, lymph node enlargement, interstitial syndrome, anemia | 106; 854; 229 (2.3) | BAL (direct -, culture -) | Paradoxical certain | ART+Itra continuation, corticosteroids (2 weeks) | Pre-ART pneumocystis coinfection (ME and DFA and PCR) |
| 5 | Colon (culture and PCR) | 42 | 25; 513; 2 946 576 (6.4) | Tenofovir, emtricitabine, atazanavir/r | 11 | Fever, chest pain, ankle arthritis, abdominal pain, anemia | NA | Not done | Paradoxical probable | ART+Itra continuation | … |
| 6 | Colon (culture) | 0 | 48; 523; 37 000 (4.5) | Tenofovir, abacavir, atazanavir/r | 50 | Extensive ulcerative and hemorrhagic colitis | 6; 120; 47 (1.6) | Colon (direct, culture) | Paradoxical probable | ART continuation, Itra continuation then LAmb, Colectomy (day 55) | Cardiac arrest (day 55), CMV coinfection (PCR) |
| 7 | Blood (culture) | 12 | 11; 65; 400 000 (5.6) | Tenofovir, emtricitabine, atazanavir/r | 6 | Fever, abdominal pain, miliary nodules, lymph node enlargement, anemia | 32; 65; 19 953 (4.3) | Bone marrow (direct -, culture -) | Paradoxical certain | ART + Itra continuation | HIV viral load done day 94 from symptoms onset, 1 log after 6 months on ART |
| 8 | Lymph nodes (culture) | 155 | 272; 2727; 165 969 (5.2) | Tenofovir, emtricitabine, raltegravir | 59 | Lymph node enlargement, cough, hepatic cytolysis | 529; 2981; 947 (2.9) | Not done | Paradoxical certain | ART + Itra continuation | … |
| 9 | … | … | 95; 335; 367 502 (5.6) | Stavudine, didanosine, nevirapine | 38 | Wasting syndrome, colonic ulcers, pleural effusion, anemia | 211; 122; 63 (1.8) | Colon (histology) | Unmasking certain | ART continuation, LAmb (2 weeks), Itra | … |
| 10 | … | … | 323; 808; 68 771 (4.8) | Lamivudine, stavudine, indinavir | 7 | Lymph node enlargement, splenomegaly, papular rash, anemia | 320; 517; 29 859 (4.4) | Lymph nodes (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load <1 log on day 30 from symptoms onset and ART discontinued |
| 11 | … | … | 113; 828; 21 190 (4.3) | Lamivudine, zidovudine, indinavir | 7 | Fever, cough, interstitial syndrome, esophageal ulcers, anemia, hepatic cytolysis | 128; 760; 500 (2.7) | Liver (culture) | Unmasking probable | ART continuation, LAmb (8 days), Itra | CD4-CD8 counts and HIV viral load done day 80 from symptoms onset |
| 12 | … | … | 21; 1448; NA | Zalcitabine, zidovudine | NA | Fever, weight loss, l ymph node enlargement, cholestasis | 19; 478; NA (NA) | Lymph nodes (histology) | Unmasking probable | ART continuation Itra (7 days), LAmb (3 days), Itra, corticosteroids | … |
| 13 | … | … | 56; NA; 147 615 (5.2) | Tenofovir, lamivudiene, efavirenz | 100 | Fever, meningoencephalitis, interstitial syndrome, diarrhea, arthralgia, anemia | 93; 367; <20 (<1.3) | CSF and blood and bone marrow (culture) | Unmasking certain | ART continuation, LAmb (3 days), Itra | … |
| 14 | … | … | 179; 1260; 22 000 (4.3) | Tenofovir, emtricitabine, elvitegravir, cobicistat | 5 | Fever, cough, diarrhea, esophageal ulcer, lymph node enlargement, focal neurologic event, DIC, adrenal insufficiency | 238; 2640; 360 (2.5) | Lymph nodes a esophagus (histology) | Unmasking certain | Itra, LAmb, Itra. ART continuation (washout 7 days) | … |
| 15 | … | … | 392; 787; 61 586 (4.7) | Lamivudine, zidovudine, lopinavir/r | 11 | Abdominal pain, antepartum hemorrhage, anemia, premature birth | NA | Placenta (culture and PCR) | Unmasking probable | ART continuation, cesarean section (week 31), Itra | Itra started 27 days after cesarean section upon culture results in an asymptomatic patient |
| 16 | … | … | 10; 128; NA (NA) | Abacavir, lamivudine, atazanavir/r | 9 | Fever, cough, lymph node enlargement, hepatomegaly, splenomegaly | NA | Lymph nodes (histology) | Unmasking probable | ART discontinuation, LAmb (14 days), Itra | MAC coinfection (histology and culture) |
| 17 | … | … | 74; 440; 1500 (3.1) | Tenofovir, emtricitabine, atazanavir/r | 9 | Fever, dyspnea and cough, lymph node enlargement, bicytopenia | 56; 267; 340 (2.5) | Blood (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load ↓ <1 log ART stopped 1 week before blood check |
| 18 | … | … | 35; 190; 2 300 000 (6.3) | Tenofovir, emtricitabine, darunavir/r | 1 | Fever, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, splenomegaly, MAS | 65; 104; 530 (2.7) | Bone marrow and blood (culture) | Unmasking probable | ART continuation, LAmb (5 days), Itra | Probable pre-ART latent histoplasmosis undiagnosed |
| 19 | … | … | 80; 1273; 1 251 258 (6.1) | Tenofovir, emtricitabine, efavirenz | 6 | Fever, weight loss, dyspnea, focal neurologic event, anemia, hepatic cytolysis | 262; 2594; 360 (2.5) | Bone marrow (culture and PCR), blood and CSF (PCR) | Unmasking certain | ART continuation, Itra (6 days), Itra+LAmb (6 days), Itra (4 days), Fluco (Itra adverse event) | CD4-CD8 counts and HIV viral load done day 58 |
| 20 | … | … | 25; 277; 32 240 (4.5) | Abacavir, lamivudine, darunavir/r | 19 | Fever, small bowel perforation, peritonitis, interstitial syndrome, anemia | 25; 153; <20 (<1.3) | Blood (culture), small bowel (histology) | Unmasking certain | ART continuation, LAmb+Itra, corticosteroids (3 weeks), small bowel resection | Consecutive IRIS episodes: severe pneumonia (day 19), small bowel perforation with peritonitis (day 69) |
| 21 | … | … | 59; NA; 353 000 (5.5) | Tenofovir, emtricitabine, lopinavir/r | 50 | Lymph node enlargement, anemia | 249; NA; 697 (2.8) | Lymph nodes (histology) | Unmasking certain | ART discontinuation, Itra | MAC coinfection (AFB smear and PCR) |
| 22 | … | … | NA; NA; 1 100 000 (6.0) | Tenofovir, emtricitabine, efavirenz | 10 | Fever, dyspnea, cough, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, MAS | 139; 478; 11 159 (4.0) | Bone marrow (culture) | Unmasking certain | ART continuation, LAmb (8 days), Itra | Probable MAS: hemodiluted bone marrow |
Abbreviations: AFB, acid-fast bacilli; ART, antiretroviral therapy; CMV, cytomegalovirus infection; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; DIC, disseminated intravascular coagulation; Fluco, fluconazole; HIV, human immunodeficiency virus; IRIS, immune reconstitution inflammatory syndrome; Itra, itraconazole; LAmb, liposomal amphotericin B; MAC, Mycobacterium Avium Complex infection; MAS, macrophage activation syndrome; ME, microscopic examination; NA, not available; PCR, polymerase chain reaction; “-”, negative direct examination or culture in mycology.
aCD4 count, CD8 count, and HIV RNA viral load represented the most recent available information within 3 months before ART initiation.
bCD4 count, CD8 count, and HIV RNA viral load available within 3 months around IRIS symptoms onset.
Clinical Presentation, Care, and Treatment of 22 Cases of Histoplasmosis-associated Immune Reconstitution Inflammatory Syndrome: French Guiana, 1 January 1997 to 30 September 2007
| Pre-ART | ART Initiation | IRIS Associated With Histoplasma capsulatum | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case Number | Histoplasmosis Diagnosis | Time of Antifungals- ART (days) | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)a | ART Regimen | Time of ART- Symptoms Onset (days) | Clinical Presentation | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)b | Histoplasmosis Diagnosis | IRIS Type and Class | Management | Comments |
| 1 | Liver (histology) | 78 | 204;1737;>500 000(>5.7) | Lamivudine, didanosine, efavirenz | 19 | Fever, dyspnea, interstitial syndrome, abdominal pain, diarrhea | 196;528;527(2.7) | Not done | Paradoxical certain | ART+Itra continuation | … |
| 2 | Colon and Pulmonary (culture) | 27 | 24; NA; 480 014 (5.7) | Lamivudine, didanosine, efavirenz | NA | Fever, weight loss, diarrhea, hepatomegaly, anemia, acute renal failure | 511; 1282; 117 (2.0) | Not done | Paradoxical probable | ART+Itra continuation | CD4-CD8 counts and HIV viral load done day 56 from hospital admission for IRIS |
| 3 | Lymph node and bone marrow (culture) | 14 | 4.9; 59; 4 000 000 (6.6) | Tenofovir, emtricitabine, darunavir/r | 43 | Fever, papular rash, lymph node enlargement, abdominal pain, diarrhea, anemia, hyperferritinemia | 102; 356; 150 (2.2) | Lymph node (direct -, culture -) | Paradoxical certain | ART+Itra continuation | … |
| 4 | Pulmonary (PCR) | 27 | 15; 29; 271 462 (5.4) | Tenofovir, emtricitabine, efavirenz | 30 | Weight loss, lymph node enlargement, interstitial syndrome, anemia | 106; 854; 229 (2.3) | BAL (direct -, culture -) | Paradoxical certain | ART+Itra continuation, corticosteroids (2 weeks) | Pre-ART pneumocystis coinfection (ME and DFA and PCR) |
| 5 | Colon (culture and PCR) | 42 | 25; 513; 2 946 576 (6.4) | Tenofovir, emtricitabine, atazanavir/r | 11 | Fever, chest pain, ankle arthritis, abdominal pain, anemia | NA | Not done | Paradoxical probable | ART+Itra continuation | … |
| 6 | Colon (culture) | 0 | 48; 523; 37 000 (4.5) | Tenofovir, abacavir, atazanavir/r | 50 | Extensive ulcerative and hemorrhagic colitis | 6; 120; 47 (1.6) | Colon (direct, culture) | Paradoxical probable | ART continuation, Itra continuation then LAmb, Colectomy (day 55) | Cardiac arrest (day 55), CMV coinfection (PCR) |
| 7 | Blood (culture) | 12 | 11; 65; 400 000 (5.6) | Tenofovir, emtricitabine, atazanavir/r | 6 | Fever, abdominal pain, miliary nodules, lymph node enlargement, anemia | 32; 65; 19 953 (4.3) | Bone marrow (direct -, culture -) | Paradoxical certain | ART + Itra continuation | HIV viral load done day 94 from symptoms onset, 1 log after 6 months on ART |
| 8 | Lymph nodes (culture) | 155 | 272; 2727; 165 969 (5.2) | Tenofovir, emtricitabine, raltegravir | 59 | Lymph node enlargement, cough, hepatic cytolysis | 529; 2981; 947 (2.9) | Not done | Paradoxical certain | ART + Itra continuation | … |
| 9 | … | … | 95; 335; 367 502 (5.6) | Stavudine, didanosine, nevirapine | 38 | Wasting syndrome, colonic ulcers, pleural effusion, anemia | 211; 122; 63 (1.8) | Colon (histology) | Unmasking certain | ART continuation, LAmb (2 weeks), Itra | … |
| 10 | … | … | 323; 808; 68 771 (4.8) | Lamivudine, stavudine, indinavir | 7 | Lymph node enlargement, splenomegaly, papular rash, anemia | 320; 517; 29 859 (4.4) | Lymph nodes (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load <1 log on day 30 from symptoms onset and ART discontinued |
| 11 | … | … | 113; 828; 21 190 (4.3) | Lamivudine, zidovudine, indinavir | 7 | Fever, cough, interstitial syndrome, esophageal ulcers, anemia, hepatic cytolysis | 128; 760; 500 (2.7) | Liver (culture) | Unmasking probable | ART continuation, LAmb (8 days), Itra | CD4-CD8 counts and HIV viral load done day 80 from symptoms onset |
| 12 | … | … | 21; 1448; NA | Zalcitabine, zidovudine | NA | Fever, weight loss, l ymph node enlargement, cholestasis | 19; 478; NA (NA) | Lymph nodes (histology) | Unmasking probable | ART continuation Itra (7 days), LAmb (3 days), Itra, corticosteroids | … |
| 13 | … | … | 56; NA; 147 615 (5.2) | Tenofovir, lamivudiene, efavirenz | 100 | Fever, meningoencephalitis, interstitial syndrome, diarrhea, arthralgia, anemia | 93; 367; <20 (<1.3) | CSF and blood and bone marrow (culture) | Unmasking certain | ART continuation, LAmb (3 days), Itra | … |
| 14 | … | … | 179; 1260; 22 000 (4.3) | Tenofovir, emtricitabine, elvitegravir, cobicistat | 5 | Fever, cough, diarrhea, esophageal ulcer, lymph node enlargement, focal neurologic event, DIC, adrenal insufficiency | 238; 2640; 360 (2.5) | Lymph nodes a esophagus (histology) | Unmasking certain | Itra, LAmb, Itra. ART continuation (washout 7 days) | … |
| 15 | … | … | 392; 787; 61 586 (4.7) | Lamivudine, zidovudine, lopinavir/r | 11 | Abdominal pain, antepartum hemorrhage, anemia, premature birth | NA | Placenta (culture and PCR) | Unmasking probable | ART continuation, cesarean section (week 31), Itra | Itra started 27 days after cesarean section upon culture results in an asymptomatic patient |
| 16 | … | … | 10; 128; NA (NA) | Abacavir, lamivudine, atazanavir/r | 9 | Fever, cough, lymph node enlargement, hepatomegaly, splenomegaly | NA | Lymph nodes (histology) | Unmasking probable | ART discontinuation, LAmb (14 days), Itra | MAC coinfection (histology and culture) |
| 17 | … | … | 74; 440; 1500 (3.1) | Tenofovir, emtricitabine, atazanavir/r | 9 | Fever, dyspnea and cough, lymph node enlargement, bicytopenia | 56; 267; 340 (2.5) | Blood (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load ↓ <1 log ART stopped 1 week before blood check |
| 18 | … | … | 35; 190; 2 300 000 (6.3) | Tenofovir, emtricitabine, darunavir/r | 1 | Fever, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, splenomegaly, MAS | 65; 104; 530 (2.7) | Bone marrow and blood (culture) | Unmasking probable | ART continuation, LAmb (5 days), Itra | Probable pre-ART latent histoplasmosis undiagnosed |
| 19 | … | … | 80; 1273; 1 251 258 (6.1) | Tenofovir, emtricitabine, efavirenz | 6 | Fever, weight loss, dyspnea, focal neurologic event, anemia, hepatic cytolysis | 262; 2594; 360 (2.5) | Bone marrow (culture and PCR), blood and CSF (PCR) | Unmasking certain | ART continuation, Itra (6 days), Itra+LAmb (6 days), Itra (4 days), Fluco (Itra adverse event) | CD4-CD8 counts and HIV viral load done day 58 |
| 20 | … | … | 25; 277; 32 240 (4.5) | Abacavir, lamivudine, darunavir/r | 19 | Fever, small bowel perforation, peritonitis, interstitial syndrome, anemia | 25; 153; <20 (<1.3) | Blood (culture), small bowel (histology) | Unmasking certain | ART continuation, LAmb+Itra, corticosteroids (3 weeks), small bowel resection | Consecutive IRIS episodes: severe pneumonia (day 19), small bowel perforation with peritonitis (day 69) |
| 21 | … | … | 59; NA; 353 000 (5.5) | Tenofovir, emtricitabine, lopinavir/r | 50 | Lymph node enlargement, anemia | 249; NA; 697 (2.8) | Lymph nodes (histology) | Unmasking certain | ART discontinuation, Itra | MAC coinfection (AFB smear and PCR) |
| 22 | … | … | NA; NA; 1 100 000 (6.0) | Tenofovir, emtricitabine, efavirenz | 10 | Fever, dyspnea, cough, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, MAS | 139; 478; 11 159 (4.0) | Bone marrow (culture) | Unmasking certain | ART continuation, LAmb (8 days), Itra | Probable MAS: hemodiluted bone marrow |
| Pre-ART | ART Initiation | IRIS Associated With Histoplasma capsulatum | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case Number | Histoplasmosis Diagnosis | Time of Antifungals- ART (days) | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)a | ART Regimen | Time of ART- Symptoms Onset (days) | Clinical Presentation | CD4 Count (/µL); CD8 Count (/µL); HIV Viral Load, Copies/mL (log)b | Histoplasmosis Diagnosis | IRIS Type and Class | Management | Comments |
| 1 | Liver (histology) | 78 | 204;1737;>500 000(>5.7) | Lamivudine, didanosine, efavirenz | 19 | Fever, dyspnea, interstitial syndrome, abdominal pain, diarrhea | 196;528;527(2.7) | Not done | Paradoxical certain | ART+Itra continuation | … |
| 2 | Colon and Pulmonary (culture) | 27 | 24; NA; 480 014 (5.7) | Lamivudine, didanosine, efavirenz | NA | Fever, weight loss, diarrhea, hepatomegaly, anemia, acute renal failure | 511; 1282; 117 (2.0) | Not done | Paradoxical probable | ART+Itra continuation | CD4-CD8 counts and HIV viral load done day 56 from hospital admission for IRIS |
| 3 | Lymph node and bone marrow (culture) | 14 | 4.9; 59; 4 000 000 (6.6) | Tenofovir, emtricitabine, darunavir/r | 43 | Fever, papular rash, lymph node enlargement, abdominal pain, diarrhea, anemia, hyperferritinemia | 102; 356; 150 (2.2) | Lymph node (direct -, culture -) | Paradoxical certain | ART+Itra continuation | … |
| 4 | Pulmonary (PCR) | 27 | 15; 29; 271 462 (5.4) | Tenofovir, emtricitabine, efavirenz | 30 | Weight loss, lymph node enlargement, interstitial syndrome, anemia | 106; 854; 229 (2.3) | BAL (direct -, culture -) | Paradoxical certain | ART+Itra continuation, corticosteroids (2 weeks) | Pre-ART pneumocystis coinfection (ME and DFA and PCR) |
| 5 | Colon (culture and PCR) | 42 | 25; 513; 2 946 576 (6.4) | Tenofovir, emtricitabine, atazanavir/r | 11 | Fever, chest pain, ankle arthritis, abdominal pain, anemia | NA | Not done | Paradoxical probable | ART+Itra continuation | … |
| 6 | Colon (culture) | 0 | 48; 523; 37 000 (4.5) | Tenofovir, abacavir, atazanavir/r | 50 | Extensive ulcerative and hemorrhagic colitis | 6; 120; 47 (1.6) | Colon (direct, culture) | Paradoxical probable | ART continuation, Itra continuation then LAmb, Colectomy (day 55) | Cardiac arrest (day 55), CMV coinfection (PCR) |
| 7 | Blood (culture) | 12 | 11; 65; 400 000 (5.6) | Tenofovir, emtricitabine, atazanavir/r | 6 | Fever, abdominal pain, miliary nodules, lymph node enlargement, anemia | 32; 65; 19 953 (4.3) | Bone marrow (direct -, culture -) | Paradoxical certain | ART + Itra continuation | HIV viral load done day 94 from symptoms onset, 1 log after 6 months on ART |
| 8 | Lymph nodes (culture) | 155 | 272; 2727; 165 969 (5.2) | Tenofovir, emtricitabine, raltegravir | 59 | Lymph node enlargement, cough, hepatic cytolysis | 529; 2981; 947 (2.9) | Not done | Paradoxical certain | ART + Itra continuation | … |
| 9 | … | … | 95; 335; 367 502 (5.6) | Stavudine, didanosine, nevirapine | 38 | Wasting syndrome, colonic ulcers, pleural effusion, anemia | 211; 122; 63 (1.8) | Colon (histology) | Unmasking certain | ART continuation, LAmb (2 weeks), Itra | … |
| 10 | … | … | 323; 808; 68 771 (4.8) | Lamivudine, stavudine, indinavir | 7 | Lymph node enlargement, splenomegaly, papular rash, anemia | 320; 517; 29 859 (4.4) | Lymph nodes (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load <1 log on day 30 from symptoms onset and ART discontinued |
| 11 | … | … | 113; 828; 21 190 (4.3) | Lamivudine, zidovudine, indinavir | 7 | Fever, cough, interstitial syndrome, esophageal ulcers, anemia, hepatic cytolysis | 128; 760; 500 (2.7) | Liver (culture) | Unmasking probable | ART continuation, LAmb (8 days), Itra | CD4-CD8 counts and HIV viral load done day 80 from symptoms onset |
| 12 | … | … | 21; 1448; NA | Zalcitabine, zidovudine | NA | Fever, weight loss, l ymph node enlargement, cholestasis | 19; 478; NA (NA) | Lymph nodes (histology) | Unmasking probable | ART continuation Itra (7 days), LAmb (3 days), Itra, corticosteroids | … |
| 13 | … | … | 56; NA; 147 615 (5.2) | Tenofovir, lamivudiene, efavirenz | 100 | Fever, meningoencephalitis, interstitial syndrome, diarrhea, arthralgia, anemia | 93; 367; <20 (<1.3) | CSF and blood and bone marrow (culture) | Unmasking certain | ART continuation, LAmb (3 days), Itra | … |
| 14 | … | … | 179; 1260; 22 000 (4.3) | Tenofovir, emtricitabine, elvitegravir, cobicistat | 5 | Fever, cough, diarrhea, esophageal ulcer, lymph node enlargement, focal neurologic event, DIC, adrenal insufficiency | 238; 2640; 360 (2.5) | Lymph nodes a esophagus (histology) | Unmasking certain | Itra, LAmb, Itra. ART continuation (washout 7 days) | … |
| 15 | … | … | 392; 787; 61 586 (4.7) | Lamivudine, zidovudine, lopinavir/r | 11 | Abdominal pain, antepartum hemorrhage, anemia, premature birth | NA | Placenta (culture and PCR) | Unmasking probable | ART continuation, cesarean section (week 31), Itra | Itra started 27 days after cesarean section upon culture results in an asymptomatic patient |
| 16 | … | … | 10; 128; NA (NA) | Abacavir, lamivudine, atazanavir/r | 9 | Fever, cough, lymph node enlargement, hepatomegaly, splenomegaly | NA | Lymph nodes (histology) | Unmasking probable | ART discontinuation, LAmb (14 days), Itra | MAC coinfection (histology and culture) |
| 17 | … | … | 74; 440; 1500 (3.1) | Tenofovir, emtricitabine, atazanavir/r | 9 | Fever, dyspnea and cough, lymph node enlargement, bicytopenia | 56; 267; 340 (2.5) | Blood (culture) | Unmasking probable | ART discontinuation (patient’s decision), Itra | HIV viral load ↓ <1 log ART stopped 1 week before blood check |
| 18 | … | … | 35; 190; 2 300 000 (6.3) | Tenofovir, emtricitabine, darunavir/r | 1 | Fever, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, splenomegaly, MAS | 65; 104; 530 (2.7) | Bone marrow and blood (culture) | Unmasking probable | ART continuation, LAmb (5 days), Itra | Probable pre-ART latent histoplasmosis undiagnosed |
| 19 | … | … | 80; 1273; 1 251 258 (6.1) | Tenofovir, emtricitabine, efavirenz | 6 | Fever, weight loss, dyspnea, focal neurologic event, anemia, hepatic cytolysis | 262; 2594; 360 (2.5) | Bone marrow (culture and PCR), blood and CSF (PCR) | Unmasking certain | ART continuation, Itra (6 days), Itra+LAmb (6 days), Itra (4 days), Fluco (Itra adverse event) | CD4-CD8 counts and HIV viral load done day 58 |
| 20 | … | … | 25; 277; 32 240 (4.5) | Abacavir, lamivudine, darunavir/r | 19 | Fever, small bowel perforation, peritonitis, interstitial syndrome, anemia | 25; 153; <20 (<1.3) | Blood (culture), small bowel (histology) | Unmasking certain | ART continuation, LAmb+Itra, corticosteroids (3 weeks), small bowel resection | Consecutive IRIS episodes: severe pneumonia (day 19), small bowel perforation with peritonitis (day 69) |
| 21 | … | … | 59; NA; 353 000 (5.5) | Tenofovir, emtricitabine, lopinavir/r | 50 | Lymph node enlargement, anemia | 249; NA; 697 (2.8) | Lymph nodes (histology) | Unmasking certain | ART discontinuation, Itra | MAC coinfection (AFB smear and PCR) |
| 22 | … | … | NA; NA; 1 100 000 (6.0) | Tenofovir, emtricitabine, efavirenz | 10 | Fever, dyspnea, cough, lymph node enlargement, abdominal pain, diarrhea, hepatomegaly, MAS | 139; 478; 11 159 (4.0) | Bone marrow (culture) | Unmasking certain | ART continuation, LAmb (8 days), Itra | Probable MAS: hemodiluted bone marrow |
Abbreviations: AFB, acid-fast bacilli; ART, antiretroviral therapy; CMV, cytomegalovirus infection; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; DIC, disseminated intravascular coagulation; Fluco, fluconazole; HIV, human immunodeficiency virus; IRIS, immune reconstitution inflammatory syndrome; Itra, itraconazole; LAmb, liposomal amphotericin B; MAC, Mycobacterium Avium Complex infection; MAS, macrophage activation syndrome; ME, microscopic examination; NA, not available; PCR, polymerase chain reaction; “-”, negative direct examination or culture in mycology.
aCD4 count, CD8 count, and HIV RNA viral load represented the most recent available information within 3 months before ART initiation.
bCD4 count, CD8 count, and HIV RNA viral load available within 3 months around IRIS symptoms onset.
At the time of IRIS, the median CD4 count was 128 cells/µL (25–75% interquartile range, 56–249; range, 6–529) among 19 of 22 cases and was 53.5 cells/µL (22.5–146.0) at the time of ART initiation among 20 of 22 cases. At the time of IRIS, CD4 trends were stable for 7 cases and increased by at least 25 cells/µL for 10 cases (4 had missing data). At the time of IRIS, trends in HIV viral load were as follows: a decrease of more than 1 log in 16 cases, stable in 2 cases, and unavailable in 4 cases. In 2 cases, HIV viral load was undetectable (<50 copies/mL) at the time of IRIS.
The median time to onset of IRIS symptoms after ART initiation was 11 days (7–40; range, 1–100) for the 22 IRIS cases, 30 days (11–50; range, 6–59) for 7 of 8 paradoxical IRIS cases, and 9 days (7–19; range, 1–100) for infectious/unmasking IRIS cases. The median time between antifungal therapy initiation and ART initiation was 27 days (13–60; range, 0–155) for paradoxical IRIS.
Clinical Presentation and Diagnosis
The main features were digestive manifestations (17/22), hematologic manifestations (17/22), and respiratory manifestations (14/22) in a context of fever (15/22). A case of localized placental histoplasmosis resulting in preterm birth was observed.
All but 1 histoplasmosis case were diagnosed by culture and/or pathology (case number 4 relied on molecular biology).
Treatment and Outcome
Among infectious/unmasking IRIS cases, the main ART regimens were 2 nucleoside reverse transcriptase inhibitors (NRTIs) associated with a protease inhibitor (PI) in 8 of 14 cases and 2 NRTIs associated with a nonnucleoside reverse transcriptase inhibitor in 4 of 14 cases. Among paradoxical IRIS cases, the main ART regimens were 2 NRTIs associated with a PI in 4 of 8 cases and 2 NRTIs associated with a nonnucleoside reverse transcriptase inhibitor in 3 of 8 cases.
Therapeutic management of infectious/unmasking IRIS cases reported ART continuation in 10 of 14 cases. ART discontinuations involved a physician decision (2 cases of coinfections) and the patient decision (2 cases). Two patients received corticosteroids. With regard to antifungal therapy, initial treatment used liposomal amphotericin B in 10 of 14 cases or itraconazole alone in 4 of 14 cases. Management of paradoxical IRIS cases reported ART continuation in all patients. With regard to antifungal therapy, itraconazole was initially continued for all patients and subsequently switched to liposomal amphotericin B in 1 case. One patient received corticosteroids in association with ART and antifungals. Surgery was performed in 3 patients: 2 cases of gastrointestinal histoplasmosis (colectomy and small bowel resection) and 1 case of placental histoplasmosis (cesarean section).
No deaths were reported in the month following IRIS symptoms onset. Two IRIS cases were classified as severe in the month following IRIS symptoms onset: 1 case of extensive acute colitis and 1 case of respiratory failure admitted in ICU.
One month after hospital admission for the first episode of IRIS, 2 patients were admitted in the ICU: one because of peritonitis (day 69) in a context of intestinal perforation following first admission in the ICU for a respiratory failure and one because of cardiac arrest during colectomy (day 55) in a context of acute extensive colitis unresponsive to antifungal therapy.
Literature Review of Histoplasmosis-associated IRIS Cases
We retrieved 22 cases of histoplasmosis-associated IRIS from the literature (13 infectious/unmasking and 9 paradoxical) [8, 12–25]. Literature review results and a detailed description of IRIS cases are available in the Supplementary Material.
In Table 2, the patients’ baseline data were similar to those of IRIS cases included in the present study (age, sex, CD4 counts at the time of IRIS), and all IRIS cases did not systematically meet the case definition regarding an increase in the CD4 count and an HIV viral load decrease. When compared with IRIS cases described in French Guiana, time to symptom onset after ART initiation was longer (60 days; range, 7–140 days) among infectious/unmasking IRIS, median time between antifungal therapy initiation and ART initiation was longer (40.5 days; range, 10.5–75.0 days) among paradoxical IRIS cases (5 missing data), and mucocutaneous manifestations were frequently reported. When available, ART regimens prescribed (9 missing data), therapeutic management of IRIS cases with ART continuation (10 missing data), therapeutic management of histoplasmosis based on international recommendations (5 missing data), and the absence of early death were similar. It is noteworthy that liposomal amphotericin B was initially prescribed in 14 of 22 IRIS cases from the literature (11 of 13 infectious/unmasking IRIS and 3 of 9 paradoxical IRIS).
Main Characteristics and Comparison of Histoplasmosis-associated Immune Reconstitution Inflammatory Syndrome Observed in French Guiana and Reported in the Literature
| IRIS French Guiana (N = 22) | IRIS Literature (N = 22) | |
|---|---|---|
| Demographics and HIV data | ||
| Mean age, y | 40.5 (±7.0) | 36.7 (±9.8) |
| Sex ratio, male:female | 1.4 | 2.1 |
| Median time to symptoms onset after ART initiation, d | ||
| All IRIS | 11 [7–40] | 51 [21–69] |
| Paradoxical only | 30 [11–50] | 30 [30–60] |
| Infectious/unmasking only | 9 [7–19] | 60 [21–90] |
| Median CD4 count at the time of ART initiation, cells/µL | ||
| All IRIS | 53.5 [22.5–146.0] | 20 [7–42] |
| Paradoxical only | 24.5 [13–126] | 32 [14–55] |
| Infectious/unmasking only | 77 [30–146] | 12.5 [5–37.5] |
| Median CD4 count at the time of IRIS, cells/µL | 128 [56–249] | 113.5 [80.5–190.0] |
| CD4 count increase (≥25 cells/µL) | 9 | 17 |
| CD4 count unchanged | 7 | 3 |
| HIV viral load decrease >1 log | 16 | 18 |
| Clinical and paraclinical characteristics | ||
| Fever | 15 | 11 |
| Weight loss | 5 | 3 |
| Digestive manifestationsa | 17 | 10 |
| Hematologic manifestationsb | 17 | 6 |
| Respiratory manifestations | 14 | 7 |
| Lymph node enlargement | 12 | 11 |
| Neurological manifestations | 3 | 3 |
| Mucocutaneous manifestations | 2 | 10 |
| Rheumatological manifestations | 2 | 2 |
| Obstetrical manifestations | 1 | 0 |
| Ocular manifestations | 0 | 1 |
| Treatment and outcome | ||
| ART discontinuation | 4c | 1 |
| Corticosteroids | 3 | 2 |
| Surgery | 3 | 2d |
| Early death (≤1 month after symptoms onset) | 0 | 0 |
| IRIS French Guiana (N = 22) | IRIS Literature (N = 22) | |
|---|---|---|
| Demographics and HIV data | ||
| Mean age, y | 40.5 (±7.0) | 36.7 (±9.8) |
| Sex ratio, male:female | 1.4 | 2.1 |
| Median time to symptoms onset after ART initiation, d | ||
| All IRIS | 11 [7–40] | 51 [21–69] |
| Paradoxical only | 30 [11–50] | 30 [30–60] |
| Infectious/unmasking only | 9 [7–19] | 60 [21–90] |
| Median CD4 count at the time of ART initiation, cells/µL | ||
| All IRIS | 53.5 [22.5–146.0] | 20 [7–42] |
| Paradoxical only | 24.5 [13–126] | 32 [14–55] |
| Infectious/unmasking only | 77 [30–146] | 12.5 [5–37.5] |
| Median CD4 count at the time of IRIS, cells/µL | 128 [56–249] | 113.5 [80.5–190.0] |
| CD4 count increase (≥25 cells/µL) | 9 | 17 |
| CD4 count unchanged | 7 | 3 |
| HIV viral load decrease >1 log | 16 | 18 |
| Clinical and paraclinical characteristics | ||
| Fever | 15 | 11 |
| Weight loss | 5 | 3 |
| Digestive manifestationsa | 17 | 10 |
| Hematologic manifestationsb | 17 | 6 |
| Respiratory manifestations | 14 | 7 |
| Lymph node enlargement | 12 | 11 |
| Neurological manifestations | 3 | 3 |
| Mucocutaneous manifestations | 2 | 10 |
| Rheumatological manifestations | 2 | 2 |
| Obstetrical manifestations | 1 | 0 |
| Ocular manifestations | 0 | 1 |
| Treatment and outcome | ||
| ART discontinuation | 4c | 1 |
| Corticosteroids | 3 | 2 |
| Surgery | 3 | 2d |
| Early death (≤1 month after symptoms onset) | 0 | 0 |
Means are presented with standard deviations (±SD) and medians are presented with 25–75% interquartile ranges in brackets. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IRIS, immune reconstitution inflammatory syndrome.
aDigestive manifestations: hepatic, splenic, or gastrointestinal involvement (ie, abdominal pain, diarrhea, hepatosplenomegaly, abscess, cytolysis).
bHematologic manifestations: anemia or bicytopenia or pancytopenia.
cART discontinuation: 2 patients’ decision.
dDigestive surgery.
Main Characteristics and Comparison of Histoplasmosis-associated Immune Reconstitution Inflammatory Syndrome Observed in French Guiana and Reported in the Literature
| IRIS French Guiana (N = 22) | IRIS Literature (N = 22) | |
|---|---|---|
| Demographics and HIV data | ||
| Mean age, y | 40.5 (±7.0) | 36.7 (±9.8) |
| Sex ratio, male:female | 1.4 | 2.1 |
| Median time to symptoms onset after ART initiation, d | ||
| All IRIS | 11 [7–40] | 51 [21–69] |
| Paradoxical only | 30 [11–50] | 30 [30–60] |
| Infectious/unmasking only | 9 [7–19] | 60 [21–90] |
| Median CD4 count at the time of ART initiation, cells/µL | ||
| All IRIS | 53.5 [22.5–146.0] | 20 [7–42] |
| Paradoxical only | 24.5 [13–126] | 32 [14–55] |
| Infectious/unmasking only | 77 [30–146] | 12.5 [5–37.5] |
| Median CD4 count at the time of IRIS, cells/µL | 128 [56–249] | 113.5 [80.5–190.0] |
| CD4 count increase (≥25 cells/µL) | 9 | 17 |
| CD4 count unchanged | 7 | 3 |
| HIV viral load decrease >1 log | 16 | 18 |
| Clinical and paraclinical characteristics | ||
| Fever | 15 | 11 |
| Weight loss | 5 | 3 |
| Digestive manifestationsa | 17 | 10 |
| Hematologic manifestationsb | 17 | 6 |
| Respiratory manifestations | 14 | 7 |
| Lymph node enlargement | 12 | 11 |
| Neurological manifestations | 3 | 3 |
| Mucocutaneous manifestations | 2 | 10 |
| Rheumatological manifestations | 2 | 2 |
| Obstetrical manifestations | 1 | 0 |
| Ocular manifestations | 0 | 1 |
| Treatment and outcome | ||
| ART discontinuation | 4c | 1 |
| Corticosteroids | 3 | 2 |
| Surgery | 3 | 2d |
| Early death (≤1 month after symptoms onset) | 0 | 0 |
| IRIS French Guiana (N = 22) | IRIS Literature (N = 22) | |
|---|---|---|
| Demographics and HIV data | ||
| Mean age, y | 40.5 (±7.0) | 36.7 (±9.8) |
| Sex ratio, male:female | 1.4 | 2.1 |
| Median time to symptoms onset after ART initiation, d | ||
| All IRIS | 11 [7–40] | 51 [21–69] |
| Paradoxical only | 30 [11–50] | 30 [30–60] |
| Infectious/unmasking only | 9 [7–19] | 60 [21–90] |
| Median CD4 count at the time of ART initiation, cells/µL | ||
| All IRIS | 53.5 [22.5–146.0] | 20 [7–42] |
| Paradoxical only | 24.5 [13–126] | 32 [14–55] |
| Infectious/unmasking only | 77 [30–146] | 12.5 [5–37.5] |
| Median CD4 count at the time of IRIS, cells/µL | 128 [56–249] | 113.5 [80.5–190.0] |
| CD4 count increase (≥25 cells/µL) | 9 | 17 |
| CD4 count unchanged | 7 | 3 |
| HIV viral load decrease >1 log | 16 | 18 |
| Clinical and paraclinical characteristics | ||
| Fever | 15 | 11 |
| Weight loss | 5 | 3 |
| Digestive manifestationsa | 17 | 10 |
| Hematologic manifestationsb | 17 | 6 |
| Respiratory manifestations | 14 | 7 |
| Lymph node enlargement | 12 | 11 |
| Neurological manifestations | 3 | 3 |
| Mucocutaneous manifestations | 2 | 10 |
| Rheumatological manifestations | 2 | 2 |
| Obstetrical manifestations | 1 | 0 |
| Ocular manifestations | 0 | 1 |
| Treatment and outcome | ||
| ART discontinuation | 4c | 1 |
| Corticosteroids | 3 | 2 |
| Surgery | 3 | 2d |
| Early death (≤1 month after symptoms onset) | 0 | 0 |
Means are presented with standard deviations (±SD) and medians are presented with 25–75% interquartile ranges in brackets. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IRIS, immune reconstitution inflammatory syndrome.
aDigestive manifestations: hepatic, splenic, or gastrointestinal involvement (ie, abdominal pain, diarrhea, hepatosplenomegaly, abscess, cytolysis).
bHematologic manifestations: anemia or bicytopenia or pancytopenia.
cART discontinuation: 2 patients’ decision.
dDigestive surgery.
DISCUSSION
With 22 cases we report a large retrospective case series of histoplasmosis-associated IRIS in PLHIV. With an overall incidence rate of 0.74 per 1000 HIV-infected person-years, histoplasmosis-associated IRIS remains rare and stable over a 20-year period despite evolutions in HIV care and treatment. This incidence rate was lower than in reports on the frequent association of IRIS with other pathogens (ie, Mycobacterium tuberculosis) among PLHIV with baseline CD4 counts of less than 200 cells/µL [26]. It is noteworthy that reviewing the medical files of all suspected cases, using a rigorous case definition and expert agreement, led to the exclusion of numerous cases and resulted in lower incidence rate estimates when compared with the previously published estimates computed from the same cohort [27].
The main clinical presentations revealed a nonspecific and disseminated expression of the disease. Upon the clinical evaluation of the patients, the only pattern observed was the rapid progression of a subclinical or a previously treated disseminated histoplasmosis following the recent introduction of ART in an asymptomatic patient. Nonetheless, we observed a very rare case of IRIS associated with a placental histoplasmosis, which, to our knowledge, has never been described. H. capsulatum infection was probably only discovered because ART initiation and IRIS occurrence were associated with preterm birth. No specific treatment was given while waiting for the results of a placental fungal culture, which was positive 1 month after delivery and was followed by antifungal therapy in an asymptomatic patient at the time. Similarly, despite being premature, the newborn infant had a favorable outcome without any antifungal therapy and no investigations were performed to diagnose histoplasmosis.
The management of paradoxical IRIS revealed that physicians did not discontinue ART and oral itraconazole for 6 of 8 patients. For 2 patients, both coinfected with Pneumocystis jirovecii or cytomegalovirus, physicians added to ART regimens a short course of corticosteroids or liposomal amphotericin B in a severe case requiring surgery, respectively. With regard to the management of infectious/unmasking IRIS, ART and antifungal continuation was the rule. Only 2 patients received corticosteroids.
We reported no deaths and complete or partial recovery for all patients at 1 month after ART initiation. Two patients were admitted to the ICU and labeled as severe (1 infectious/unmasking and 1 paradoxical IRIS). When considering the use of liposomal amphotericin B as a proxy for histoplasmosis-associated IRIS severity, we can add 9 severe IRIS cases, all infectious/unmasking out of 1 paradoxical IRIS, for a total of 11 of 22 IRIS cases that were severe or at least generated marked morbidity levels.
When comparing histoplasmosis-associated IRIS cases in our study with those published to date, the main clinical presentations showed the same nonspecific and disseminated disease pattern. Still, mucocutaneous manifestations were more frequent in cases reported in the literature. Median time to IRIS after ART initiation was similar in both groups of paradoxical IRIS (30 days). The difference in the median time to ART after antifungal initiation (27 days in our study versus 40.5 days in the literature) may have no influence on the outcome. On the other hand, among infectious/unmasking IRIS cases, median time to IRIS after ART initiation was 6 times longer in cases from the literature (60 days) compared with those in our study (9 days), perhaps because of a lack of awareness of histoplasmosis. The influence of ART regimens on the occurrence of IRIS, notably the presence of PIs, was not significant in our study and was not evaluated because of missing data in IRIS cases from the literature. No deaths occurred in the month following IRIS symptom onset in both case series. Similarly, both case series reported 1 patient each with 2 consecutive episodes of histoplasmosis-associated IRIS [23], an unusual but previously reported situation [28, 29].
The management of IRIS cases is not standardized and may depend on the causative pathogen, disease, and IRIS pathogenesis. When considering paradoxical IRIS, authors report that an initial “wait-and-see” attitude in the case of nonsevere tuberculosis-associated IRIS remains an interesting strategy since the outcome was favorable regardless of the therapeutic strategies employed [30]. However, for instance, this wait-and-see strategy may not be applicable to cryptococcal meningitis paradoxical IRIS [31]. On the other hand, in case of infectious/unmasking IRIS, the treatment of the causative pathogen together with ART continuation is probably the rule. The impact of corticosteroids on IRIS outcome is either unclear or useless.
To our knowledge, with regard to histoplasmosis-associated IRIS care and treatment, there are no recommendations based on prospective cohorts or trials. Hence, time to ART after antifungal therapy is not clearly evaluated, exposing patients to paradoxical IRIS. The Infectious Diseases Society of America recommendations [9] stated that there are no reasons to wait over 1 month to introduce ART, mainly because PLHIV at the advanced stage of HIV disease are at greater risk of experiencing lethal opportunistic infections. A 2-week delay after antifungal initiation together with significant clinical improvements in PLHIV experiencing HIV-associated histoplasmosis might be a reasonable minimum to avoid intense inflammatory responses. Furthermore, whether or not ART should be initiated according to the level of Histoplasma antigen concentration in the blood has never been assessed.
Reports on infectious/unmasking histoplasmosis-associated IRIS give insights on the need for effective and simple rapid diagnostic tests, to test and treat all PLHIV at the advanced stage of HIV disease in endemic areas for H. capsulatum before ART initiation. Only 1 Histoplasma antigen rapid diagnostic test in urine is commercially available but not yet fully distributed in endemic areas [32], and the developments on interferon-γ release assay (IGRA) to detect latent H. capsulatum infection are promising [33]. Hence, to our knowledge, there are no reports on systematic screening studies regarding HIV-associated histoplasmosis. On the other hand, in the past 2 decades, diagnosis and screening strategies for tuberculosis and cryptococcosis improved markedly in PLHIV with tests such as IGRAs, GeneXpert MTB/RIF system (Cepheid, Inc.), lateral flow lipoarabinomannan assay for tuberculosis, and lateral flow antigen assay for cryptococcosis [32].
Reports of severe cases of infectious/unmasking histoplasmosis-associated IRIS also call for the implementation of histoplasmosis primary prophylaxis in endemic areas. This attitude may avoid morbidity due to the flare-up of latent or subclinical HIV-associated histoplasmosis at the time of ART initiation. Following Infectious Diseases Society of America guidelines, itraconazole prophylaxis is recommended in PLHIV with a CD4 count of less than 150 cells/µL in endemic areas with a histoplasmosis incidence of more than 10 cases per 100 patient-years [9].
Our study has limitations due to its retrospective design. Data were missing and the oldest medical files were difficult to review due to poor storage conditions, leading to underestimate the incidence of cases, severe forms, or deaths. Four cases of coinfections with pathogens that are often responsible for IRIS were included. Still, we attempted to minimize classification bias through the use of rigorous case definitions and experts’ agreement.
Conclusions
In our study, we described 44 histoplasmosis-associated IRIS cases, including a single case series of 22 cases from French Guiana. In endemic areas, physicians should be aware of histoplasmosis-associated IRIS and its potential severe developments where the patient’s vital prognosis is at risk.
Improvements in diagnostic tests for the detection of H. capsulatum are required in order to screen asymptomatic or pauci-symptomatic PLHIV for a latent or subclinical disease before ART initiation. World Health Organization and national HIV guidelines should consider adding histoplasmosis to their advanced HIV disease package of care.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Author contributions. A. M.: literature search, study design, data collection, data analysis, data interpretation, writing, figures and tables, and revising; R. d. R. d. S. M.: literature search, study design, data collection, writing, figures and tables, and revising; B. N. and D. B.: data collection, writing, and revising; F. D., L. E., M. D., and P. C.: writing and revising; M. N.: data collection, data analysis, writing, and revising; A. A.: literature search, study design, data analysis, data interpretation, writing, figures and tables, and revising.
Financial support. This work was supported by an Investissement d’Avenir grant from the Agence Nationale de la Recherche (CEBA: ANR-10-LABX-25-01) to A. A. A. A. is supported by the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales—Agence Autonome de l’Institut National de la Santé et de la Recherche Médicale (ANRS-Inserm number 12260) and by the European Union (PO FEDER 2007–2013; number Présage: 31 362, Guyane Française).
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
