More than 80% of the world’s population lives in low-income and middle-income countries, yet access to critical care remains limited in these regions. Infectious diseases, especially human immunodeficiency virus, tuberculosis, and malaria, remain leading causes of critical care admissions and are associated with high mortality. Early recognition and timely initiation of appropriate therapies are important in improving outcomes. In this article, we aim to highlight the burden of disease, clinical presentation, diagnostic strategies, and management principles for these diseases in critically ill patients.
Key points
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Human immunodeficiency virus, tuberculosis, and malaria are major drivers of critical illness in low-income and middle-income countries, with significantly higher mortality rates than in high-income countries.
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Prompt recognition and treatment of these diseases is linked to better survival.
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Management may be complicated by confounding clinical presentations, drug interactions, and drug toxicities, requiring a multidisciplinary approach in the care of these patients.
Abbreviations
| ARDS | acute respiratory distress syndrome |
| ART | antiretroviral therapy |
| CAP | community-acquired pneumonia |
| CNS | central nervous system |
| DHA | dihydroartemisinin |
| HIV | human immunodeficiency virus |
| ICU | intensive care unit |
| IRIS | Immune reconstitution inflammatory syndrome |
| LMIC | low-income and middle-income countries |
| OI | opportunistic infection |
| pfHRP | Plasmodium falciparum histidine-rich protein |
| PJP | Pneumocystis jirovecii pneumonia |
| PWH | People living with HIV |
| RDT | rapid detection test |
Introduction
A key pillar of global health is health equity among nations and for all people. Encompassed in this definition is global critical care, with a focus on access to care for acute, life-threatening illnesses. In high income nations, care for critically ill patients typically occurs in dedicated intensive care units (ICUs), with specialized staff and use of high-cost technology.
Numerous definitions for an ICU are found in the literature. A widely referenced definition is an organized system for the provision of care to critically ill patients that provides intensive and specialized medical and nursing care, an enhanced capacity for monitoring, and multiple modalities of physiologic organ support to sustain life during a period of acute organ system insufficiency . The availability of ICU care in low-income and middle-income countries (LMIC) is limited, and care of critically ill patients frequently takes place outside of dedicated critical care units. ,,, LMIC comprise more than 80% of the world’s population but have the least access to critical care, and have higher rates of mortality when compared to high income countries. ,,,, In a meta-analysis of ICU capacity in LMICs, primarily in African countries, the ratio of ICU beds to hospital beds was 1.5%, compared to consensus recommendation of about 5%. , Available data show that there are between 0.1 and 2.5 ICU beds per 100,000 people in LMICs compared to 5 to 30 beds per 100,000 people in high-income countries, and 3.6 per 100,000 in Asian countries and regions across various economic strata. , Skilled critical care health care workers are also scarce in LMICs. In a systematic review article, about 50% of critical care services were delivered outside of a defined ICU, while 44% of the included studies had a general doctor delivering critical care services. There is sparsity of data on the availability of other critical care professionals such as nurses, respiratory therapists, and clinical pharmacists in LMICs.
A factor common to the etiology of critical illness in LMIC is the double burden of noncommunicable diseases and ongoing epidemics in communicable diseases such as human immunodeficiency virus (HIV) infection, tuberculosis (TB), malaria, and more recently, the coronavirus disease- 2019 (COVID-19) pandemic. , In this article, we begin with a brief overview of the etiology of critical care admissions in LMIC then highlight the role of HIV, TB, and malaria for the critical care physician working in a global health context.
Etiology of critical care admissions in low-income and middle-income countries
The burden of critical care illness in LMIC has not been well described due to the limited number of critical care facilities, few resources to support data collection and research, as well as the more universal challenge of defining and capturing critical illness syndromes accurately. , In an international audit of the burden of critical care illness, only 62 of 730 participating centers were from LMIC.
Available data suggest a high prevalence of infection as a cause of critical illness. In a point-prevalence study of critical illness in hospital admitted patients across 22 African countries, 12.5% of patients met the definition of critical illness. Of these, 12.6% were known to be living with HIV, while 6.9% had a diagnosis of tuberculosis. One in 4 patients had infection as the admitting diagnosis, though noncommunicable diseases were the main contributor to critical illness at 53.7% of cases. Infections, including HIV, were associated with an increased mortality risk. In a prospective, registry-based observational study of critical care admissions in Kenya, 4% of patients were found to be HIV positive. In a similar study done in Uganda, sepsis/septic shock contributed to 21.7% of the causes of critical illness, with 10% of patients known to be living with HIV, with HIV diagnosis associated with a higher risk of mortality. An observational study from Tanzania showed that 24.4% of ICU admissions were due to an infectious cause, with septic shock being the leading cause of ICU-related mortality. The proportion of nonsurvivors with HIV was 14.1%, compared to 5.3% in survivors. A similar study in South Africa showed infectious diseases contributing to 21.5% of the causes of admission to ICU. The proportion of patients with HIV in those admitted to critical care emergently (that is, not planned as part of postoperative care) was 20.2%. Taken together, these studies demonstrate that infections are a common cause of critical illness in Africa, and a leading contributor to death in those admitted to the ICU. HIV and TB are frequent comorbid conditions, and HIV has been associated with increased mortality.
While granular data regarding non-HIV/non-TB causes of critical care admission in Africa are limited, available data suggest trauma and cardiovascular disease as other common indications for admission to the ICU, with trauma contributing between 14% to 29% of admissions in some settings, , and cardiovascular disease such as myocardial infarction, heart failure, and strokes comprising one-third of admissions in others. , Recent infectious disease outbreaks have also contributed to ICU admissions in Africa, including the COVID-19 pandemic and epidemics of viral hemorrhagic fevers such as Ebola and Marburg. ,, In contrast, a diversity of conditions drive admissions to the ICU in high-income countries, including cerebrovascular and cardiovascular events, respiratory failure from a plurality of etiologies, and intoxication. ,,, When sepsis is the cause of admission, it typically occurs in older patients, and TB and HIV are rarely underlying conditions. ,,
Studies addressing the causes of ICU admission from Latin America are sparse. In a systematic review of the profile of admissions in critical care units in Brazil, 67% of the included studies had cardiovascular disease listed as the main cause of ICU admission. Only 2 of 27 studies listed infection as the main cause of critical care illness. Across LMIC countries in Asia, data suggest majority of the ICU admissions are due to noncommunicable diseases. In a point prevalence study across ICUs in India, 83% of the admissions to the medical ICU were due to noncommunicable disease, with sepsis being the cause of admission in 15%. Three percent had confirmed tropical infections, though these were not further defined. In a retrospective multi-entre study in Vietnam, respiratory tract infections played a larger role, with 22% of the ICU mortalities occurring in those admitted with an infectious disease. In a retrospective study across ICUs in Nepal, pneumonia and sepsis were the top 2 indications for ICU admission.
Human immunodeficiency virus in the global intensive care unit
People living with HIV (PWH) are at risk for critical illness due to opportunistic infections (OIs) as well as comorbid conditions such as cardiovascular disease and non-acquired immunodeficiency syndrome (AIDS) defining cancers. The proportion of PWH admitted to the ICU varies by geographic location. In the studies previously highlighted, this may range from as high as 20% in South Africa to as low as 0.5% in studies across Asia. HIV diagnosis may be known at admission though data suggest that up to 40% of diagnoses are new, with 50% not on antiretroviral therapy (ART) at the time of admission. Studies in LMIC settings show that the causes of ICU admission in PWH or newly diagnosed with HIV are mostly HIV-related. In an Ugandan study of PWH admitted to the ICU, the admission diagnoses included sepsis (21%), Pneumocystis jirovecii pneumonia (PJP) (21%), and pulmonary TB (18%). In a review of ICU admissions at a South African hospital, 204 (22.6%) out of 903 patients were HIV positive. In those with HIV, sepsis was the predominant reason for ICU admission (46.6%) with 57% of the sepsis cases being attributed to a lower respiratory tract infection (LRTI). Other infections included TB (16%), PJP (7.4%), and malaria (6.3%). In a Brazilian study of PWH admitted to ICUs, 54.5% of patients had an admitting diagnosis of sepsis. OIs were the main causes of admission (60%), of which 43% were due to PJP and 25% due to TB. Outcomes of ICU admission have been worse in PWH, with higher mortality associated with advanced HIV disease. One study demonstrated a 38% ICU mortality for those with recent advanced HIV diagnosis compared to 22% in those without advanced HIV.
Clinical Manifestations
Several overlapping infectious syndromes lead to critical care admissions in PWH. The most common manifestation of critical care illness in PWH in LMIC is sepsis, followed by respiratory failure. ,,, The most common site of infection has been the LRTI, with bacterial pneumonia being the most common cause. Neurologic manifestations such as altered level of consciousness and seizures may also lead to critical care admission in PWH. ,
Regarding specific microbiological diagnosis, OIs, especially PJP and TB, are among the most common causes. ,,, Though not limited to critical care, a systematic review of causes of hospital admissions in PWH also revealed similar patterns. The most common cause of hospital admission was tuberculosis, followed by bacterial pneumonia and bloodstream infections.
Sepsis
Sepsis/septic shock in PWH has a broad differential. In LMIC, specific considerations for the underlying etiology would include bacterial pneumonia (including invasive pneumococcal disease), gram negative bacteraemias including nontyphoidal Salmonella, disseminated TB and TB mycobactaeremia, malaria and disseminated cryptococcal disease. ,,, A systematic review and meta-analysis of etiology and outcomes of sepsis in Africa found that most patients were HIV infected, and where sought, Mycobacterium tuberculosis was the most common blood stream infection. Again, HIV was associated with increased mortality. Though these were critically ill patients, with pooled mortality rates of 19% to 39% of patients, it was not evident from most data where their care took place. In 2 randomized controlled trials (RCT) that were included, only 1% of patients with sepsis were treated in the ICU.
Respiratory infections
Community Acquired Pneumonia (CAP) remains one of the most common indications for admission to ICU in PWH. , Streptococcus pneumoniae has been the most common pathogen in studies where the microbiologic etiology is sought, , though other studies suggest that viral pathologies such as human metapneumovirus may predominate. TB may present as CAP and should be on the differential diagnosis even in nonclassical presentations. TB is discussed in detail in a later section. PJP is a common cause of respiratory failure leading to ICU admission in PWH. ,,,,, In these studies, PJP comprised 20% to 40% of all opportunistic infections that lead to critical care admission. Several other infections can present with severe pneumonia/respiratory failure/ARDS in PWH. These include unusual bacterial infections such as Mycobacterium avium complex, nocardiosis, Rhodococcus , fungal infections such as cryptococcosis and histoplasmosis, and viral infections such as influenza and severe acute respiratory syndrome- coronavirus 2 (SARS-CoV-2). These less common etiologies should be explored if the patient is not improving despite empiric treatment with a negative workup for the more typical causes.
Central nervous system infections
PWH may be admitted to the ICU with altered level of consciousness, seizures, or lateralizing signs due to meningoencephalitis and/or space occupying lesions. Studies estimate that 13% to 35% of critical care admissions in PWH are for central nervous system (CNS) infections. ,,, Cryptococcal meningitis is the most common cause of meningitis and meningoencephalitis in PWH with advanced HIV, accounting for up to 68% of such cases. There is usually a preceding history of several weeks of headache, fever and blurring of vision. Altered mental status is a late manifestation and is associated with markedly elevated intracranial pressure. Tuberculous meningitis is the second most common cause of CNS infections in PWH. TB is discussed in detail in a later section. Toxoplasma gondii may present with seizures and altered mental status, with more severe forms causing rapidly progressing encephalitis. , Disseminated toxoplasmosis may present with acute respiratory failure and shock, and is associated with a mortality rate of 78%. Brain MRI typically reveals ring enhancing lesions with a predilection for the basal ganglia. The differential diagnosis for a mass lesion in the brain in PWH is wide and includes TB, cryptococcosis, CNS lymphoma, pyogenic brain abscess among several others. Acute bacterial meningitis by S pneumoniae may lead to ICU admission, though the prevalence is low. Syphilis and cytomegalovirus are other rare causes of an encephalitic or encephalopathic process but should be considered in the differential diagnosis.
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) may complicate the treatment and outcomes of ICU admitted PWH. The most common form is unmasking IRIS, where the initiation of ART results in unmasking ” of previously undiagnosed OIs. Paradoxic IRIS occurs when there is worsening of symptoms and signs attributed to an OI that is already under treatment once ART is initiated. The most common OI associated with IRIS are TB and cryptococcal meningitis, though any infection has the potential to be associated with IRIS. In one meta-analysis, IRIS secondary to TB and cryptococcal meningitis were associated with mortality rates of 3.2% and 20.8%, respectively. Treatment with corticosteroids is indicated for TB-associated IRIS , but not in cryptococcal IRIS, due to the association of steroids with adverse events and disability.
Noninfectious causes
Malignancies such as non-Hodgkin lymphoma, Kaposi Sarcoma, and human herpes virus-8 (HHV-8) related Castleman’s disease may present in various organs and mimic infections and should be kept in the differential diagnosis of the critically ill patient with HIV.
Diagnosis
The differential diagnosis for PWH in critical care presenting with sepsis, respiratory failure, or altered mental status is broad. Accordingly, testing should include not only respiratory and blood cultures, but targeted testing for OIs. It is notable that 7% to 21% of HIV diagnoses are new at admission. ,, Universal testing for HIV should be considered in LMIC settings where the burden of HIV is typically the highest. CD4 cell counts give a risk assessment for OIs, while HIV viral load gives a baseline before ART initiation for those who are ART naïve ( Table 1 ).
Table 1
Opportunistic infections in people living with human immunodeficiency virus admitted to the intensive care unit: diagnosis and treatment
Adapted from Barbier F, Mer M, Szychowiak P, et al. Management of HIV-infected patients in the intensive care unit. Intensive Care Med 2020;46:329–42. https://doi.org/10.1007/s00134-020-05945-3 ; and Adult and Adolescent OIs HIV Clinical Guidelines | NIH [Internet]. 2025 [cited 2025 Sep 9]. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/ .
| Opportunistic Infection | Diagnosis | First-Line Treatment | Alternative and Adjunctive Therapies |
|---|---|---|---|
| PJP |
BAL fluid is the preferred specimen. Staining with Grocott-Gomori methenamine silver, Giemsa, and direct immunofluorescence. (Sensitivity >90%, Specificity >99%)
PCR is highly sensitive but may not differentiate between colonization vs disease |
TMP (15–20 mg/kg/day) + SMX (75–100 mg/kg/day) IV for 3 wk |
Pentamidine IV 4 mg/kg/day (for TMP-SMX intolerance)
Clindamycin IV 600 mg q6h or 900 mg q8h + Primaquine 30 mg base Corticosteroids if PaO 2 <70 mm Hg, A-a gradient ≥35 |
| TB |
Specimen: BAL, sputum, other clinical specimens.
AFB smear, culture, nucleic acid amplification tests, histology, urinary LAM |
See below |
CNS disease: dexamethasone
IRIS-prednisone (may be given prophylactically) |
| Cerebral toxoplasmosis |
Positive IgG serology
PCR of CSF and blood (Sensitivity 50%, Specificity 96%–100%) Brain biopsy may be required where diagnosis is unclear. Immunoperoxidase staining increases sensitivity |
Pyrimethamine 200 mg PO once, then 50–75 mg PO daily + sulfadiazine 1000–1500 mg PO q6h + leucovorin 10–25 mg PO daily for >6 wk |
Pyrimethamine + clindamycin or TMP-SMX; Corticosteroids if mass effect
Antiseizure medication for those who present with seizures |
| Cryptococcal meningoencephalitis |
CSF for culture, cryptococcal antigen (highly sensitive and specific); PCR has lower sensitivity when fungal burden is low.
Blood cultures and serum cryptococcal antigen as disease is often disseminated |
Induction: Liposomal amphotericin B (3–4 mg/kg IV daily) + flucytosine 25 mg/kg q6h for >2 wk.
Consolidation: Fluconazole 800 mg daily for >8 wk |
Liposomal amphotericin B 10 mg/kg single dose on day 1. Followed by flucytosine 25 mg/kg q6h plus fluconazole 1200 mg daily for 2 wk
Multiple regimens have been studied. Therapeutic lumbar punctures to decrease raised ICP have mortality benefit |
Abbreviation: AFB, acid fast bacilli; BAL, bronchoalveolar lavage fluid; CSF, cerebrospinal fluid; ICP, intracranial pressure; IgG, immunoglobulin G; IV, intravenous; LAM, lipoarabinomannan. PCR, polymerase chain reaction; PO, per oral; SMX, sulfamethoxazole; TMP, trimethoprim.
Treatment
Treatment is geared toward the identified infection in similar fashion to those without HIV. In general, treatment of the identified OI is started before initiating ART to avoid IRIS. For TB, initiation of ART within 2 weeks of starting antituberculous (anti-TB) medications is recommended in those with CD4 counts less than 50 cells/mm 3 where TB meningitis is not suspected. For those with higher CD4 counts, initiation of ART within 2 to 8 weeks is recommended. For TB meningitis, at least 2 weeks of anti-TB therapy should have been given, alongside dexamethasone, before starting ART. For cryptococcal meningitis, ART is deferred to 4 to 6 weeks after initiation of antifungal treatment based on a trial that demonstrated higher mortality when ART was initiated at 1 to 2 weeks.
In general, early ART initiation is the standard of care with the exceptions noted earlier. Interruption of ART is discouraged and has been linked to adverse outcomes including viral rebound, acute retroviral syndrome, decline in CD4 count, HIV disease progression and the development of drug resistance. In a clinical trial, early initiation of ART in ICU admitted patients who were newly diagnosed with HIV or not on ART were randomized to either start ART within 5 days of ICU admission or start after discharge from ICU. The primary outcome was in-hospital mortality. The study was stopped before the sample size was achieved due to slow accrual, but, in those randomized, no difference was demonstrated in mortality. Initiation or continuation of ART in the critical care setting can be challenging for several reasons, including lack of intravenous formulations when the enteral route is compromised, dose adjustments for renal and hepatic dysfunction, drug-drug interactions, adverse effects that may compound manifestations of critical illness, and IRIS for those who are ART naïve or who were on previously failing regimens. Nevertheless, it is frequently necessary to start ART in the critical setting especially with prolonged admissions as benefits outweigh the risks. Due to the complexity of initiating or continuing ART in critically ill patients, consultation with a clinician experienced in care of PWH is recommended. Use of drug interaction resources is recommended due to the number and complexity of drug interactions ( Table 2 ).
Table 2
Adverse effects and drug interactions of note associated with antiretroviral therapy
Adapted from Barbier F, Mer M, Szychowiak P, et al. Management of HIV-infected patients in the intensive care unit. Intensive Care Med 2020;46:329–42.
| Drug Class/Example Agents | Notable Severe Adverse Effects | Important Drug–Drug Interactions (Intensive Care Unit-Relevant) | Alternative Formulations or Administration Notes |
|---|---|---|---|
| NRTIs |
Abacavir: Hypersensitivity reactions (screen for HLA-B∗5701 before starting)
Lamivudine/Emtricitabine: Rash, neutropenia (rare) Zidovudine: Bone marrow suppression, myopathy, lactic acidosis, and hepatitis Tenofovir: Renal toxicity including Fanconi-like syndrome; hepatitis |
Zidovudine: Rifamycins (will decrease AZT concentrations) valproic acid, fluconazole (will increase AZT concentrations) |
Abacavir- liquid form
Lamivudine, Emtricitabine: liquid form, crushable tablets Zidovudine: oral liquid form, crushable tablets, and intravenous form Tenofovir: Crushable tablets |
| NNRTIs |
Efavirenz: Hepatitis, severe rash, and neuropsychiatric symptoms
Nevirapine: Rash, hepatotoxicity, and hypersensitivity reactions Rilpivirine/Etravirine: Rash, hepatitis, and bone marrow suppression (rare) |
All have significant CYP450 interactions.
Efavirenz: Strong inducer/inhibitor—monitor sedatives, anticonvulsants, and anticoagulants Check with interaction checker for all NNRTIs |
Efavirenz: Crushable tablets
Nevirapine: Oral liquid available Rilpivirine: oral formulation, IM formulation in combination with cabotegravir |
| INSTIs | Rash, hepatitis (rare) |
Chelation with polyvalent cations (antacids and iron supplements)
Rifampin, anticonvulsants such as phenytoin and carbamazepine decrease drug levels |
Dolutegravir: crushable tablet
Raltegravir: oral liquid formulation, and crushable tablet |
| Protease inhibitors (ritonavir-boosted or cobicistat-boosted) | Atazanavir: Hyperbilirubinemia, QT prolongation, renal stones; Lopinavir: hypersensitivity, hepatitis; Darunavir; rash, and peripheral neuropathy | Strong CYP3A4 inhibitors → multiple interactions with sedatives, anticoagulants, anticonvulsants, and antifungals | Darunavir and Lopinavir have oral liquid formulations |
|
Fusion inhibitors
Enfuvirtide |
Injection site reactions, myalgia, neuropathy, and rare pulmonary toxicity | Minimal | Subcutaneous injection only |
| CCR5 Antagonists Maraviroc | Anemia, rash | Rifamycins, anticonvulsants (phenytoin, carbamazepine, and phenobarbital) decrease maraviroc concentrations | Oral liquid formulation available |
Abbreviations: AZT, zidovudine; CCR5, C-C chemokine receptor-5; CYP, cytochrome P450; HLA, human leukocyte antigen; IM, intramuscular; INSTI, integrase strand transfer inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors.
Outcomes
In high income countries, a significant drop in mortality has been demonstrated over time in critically ill PWH. In a study from Australia and New Zealand, crude hospital mortality reduced from 36% in the period 1993 to 2002%, to 14% in 2013 to 2022. In a study from Spain, the ICU mortality reduced from 14% in 2006 to 2015%, to 7% in 2016 to 2019. The in-hospital mortality rate dropped from 20% to 13%. A similar study in the United Kingdom demonstrated a decrease in the odds of in-hospital mortality of about 10% per year over a 20-year period. However, such improvements have not been replicated in critically ill PWH in LMIC, with recent studies demonstrating an ICU mortality rate of 32% to 57%. ,, Septic shock and respiratory failure requiring mechanical ventilation are the main factors associated with mortality.
Human immunodeficiency virus in the global intensive care unit
| Key Area | Summary |
|---|---|
| Burden of disease | HIV remains a significant contributor to critical illness in low-income and middle-income countries. |
| Typical resentations | Sepsis and respiratory failure are the most frequent presentations of critical illness among people with HIV. |
| Leading OIs | Tuberculosis, PJP, and Cryptococcal meningitis are the leading opportunistic infections resulting in ICU admission. |
| ART | ART initiation or continuation is critical but requires complex decision-making regarding timing, drug interactions, and patient stability. Involve a clinician experienced in HIV management. |
Tuberculosis
TB is a leading contributor to critical care admissions in LMIC, especially in the setting of HIV, where TB is the main cause of death. It is estimated that 1.5% of adults with active TB will develop refractory hypoxaemia requiring mechanical ventilation. The proportion of hospitalized patients with TB who required ICU admission was estimated at 3.4% in 1 systematic review. TB may also be incidentally discovered in people admitted to the critical care for other reasons, especially in endemic countries. In a study in Cape Town, South Africa, 50% of patients with microbiologically confirmed TB had an indication for ICU admission unrelated to pulmonary TB. These included surgical indications, sepsis, stroke, and organ failure among others. Associated mortality from older data is high, ranging from 33% to 67% in those who are mechanically ventilated. ,
Clinical Presentation
The most common presentation of TB in critical illness is respiratory failure and acute respiratory distress syndrome (ARDS) in patients with pulmonary or disseminated tuberculosis. A systematic review and meta-analysis estimated that 36.3% of patients with TB admitted to the ICU had a diagnosis of respiratory failure/ARDS. TB may also present as septic shock. One study found tuberculosis to be the leading cause of bloodstream infections in septic shock. Though rare, sepsis and septic shock from disseminated TB have been described and is associated with high mortality, perhaps related in part to late recognition. , TB may also present with neurologic manifestations such as coma, encephalopathy, and seizures when TB meningitis is present. Other manifestations may include massive haemoptysis, cardiac tamponade, and constrictive pericarditis due to TB pericarditis, and adrenal insufficiency in the setting of disseminated TB. Multiorgan dysfunction has also been described. ,,,
Diagnosis
For those not known to have TB a priori, diagnosis of TB can be challenging, especially with extrapulmonary disease. Microbiological confirmation is pursued using a variety of methods including staining for acid-fast bacilli, PCR techniques such as Xpert MTB, histology and culture. Often a composite of several investigations is used (including suggestive imaging) in the absence of microbiological confirmation, which is difficult in extrapulmonary tuberculosis. , In a study on the burden of tuberculosis in intensive care units in Cape Town, the specificity, positive predictive value, and negative predictive value for PTB GeneXpert (using culture as the gold standard) were 93.8%, 68.8%, and 100%, respectively. Those for smear microscopy were 100%, 100%, and 91·5%. Using GeneXpert increased the yield in smear negative, culture positive patients by 55%. HIV positivity did not seem to affect the diagnostic accuracy in either group. It is worth noting that interferon-gamma release assays are neither sensitive nor specific in the diagnosis of TB disease and are not recommended diagnostic tools for this indication. , Urinary LAM is a rapid diagnostic test for TB that uses detection of part of the mycobacterial cell wall polysaccharide in urine. It has been used as an adjunct test where TB is suspected, with overall low sensitivity (40%–60%), and better sensitivity (70%–95%), with better test performance in patients with advanced HIV disease. ,,
Treatment
Treatment regimens for TB have been well described in various guidelines, with the World Health Organization (WHO) guidelines updated in 2025. , Though beyond the scope of this article, rifampin-resistant TB is a challenge to successful treatment of TB. About 3.2% of patients with a new diagnosis of TB and 16.1% of those who have previously been treated will have rifampin-resistant TB. This burden is especially high in LMIC regions including India, Indonesia, and the Philippines.
Administration of anti-TB medication in the critical illness setting may be challenging. Lack of enteral access, limited availability of IV formulations of anti-TB medication, adverse effects from drugs, and drug–drug interactions may limit the ability to initiate or continue anti-TB medication in critical care. In a retrospective multicentre study examining anti-TB drug administration in the ICU, only 48.4% of patients had anti-TB medication started during their admission. Intravenous anti-TB drug administration was associated with a lower mortality rate. Hepatotoxicity and peripheral neuropathy are common complications of anti-TB therapy and may limit the use of anti-TB medication. Rifampicin, a core component of anti-TB regimens is a potent cytochrome p450 inducer and has several drug interactions that may complicate management.
The role of glucocorticoids for extrapulmonary manifestations of TB is unclear. In a recent RCT, use of adjunctive dexamethasone did not reduce mortality in PWH with TB meningitis. This is in contrast to an earlier RCT, which had suggested reduction in mortality, though this was predominantly in HIV-negative patients. In an RCT examining prednisone for TB pericarditis in PWH, use of prednisone was associated with a lower incidence of constrictive pericarditis and hospitalization but a higher incidence of AIDS-associated cancers. A recent meta-analysis looking at efficacy and safety of glucocorticoids in tuberculosis affecting PWH showed no reduction in all-cause mortality with steroid use.
Though 4-month regimens are recommended in the WHO guidelines, the trials typically did not involve critically ill patients or those with more severe forms of TB, and therefore, these are not recommended for critically ill patients with tuberculosis ( Table 3 ). ,
Table 3
Summary of WHO recommendations on drug-susceptible tuberculosis treatment
Source WHO consolidated guidelines on tuberculosis. Module 4: Treatment and care. World Health Organization, 2025.
| Section | Recommendation |
|---|---|
| Treatment of drug-susceptible TB using a 6-mo regimen | New patients with pulmonary TB should receive a regimen containing 6 mo of rifampicin: 2HRZE/4HR (strong recommendation and high certainty of evidence). |
| The optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy (strong recommendation and high certainty of evidence). | |
| Thrice-weekly dosing is not recommended in both the intensive and continuation phases. Daily dosing remains the standard (conditional recommendation and very low certainty of evidence). | |
| FDC tablets are preferred over separate drug formulations (conditional recommendation, low certainty of evidence). | |
| Extension of the intensive phase is not recommended if sputum smear is positive at the end of the intensive phase (strong recommendation, high certainty of evidence). | |
| Treatment of drug-susceptible TB using 4-mo regimens | People aged 12 y or older with drug-susceptible pulmonary TB may receive a 4-mo regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (2HPMZ/2HPM) (conditional recommendation, moderate certainty of evidence). |
| Children and adolescents (3 months–16 years) with nonsevere TB should receive a 4-mo regimen (2HRZ(E)/2HR) (strong recommendation, moderate certainty of evidence). | |
| TB treatment and ART in people living with HIV | TB patients living with HIV should receive at least the same duration of TB treatment as HIV-negative patients (strong recommendation, high certainty of evidence). |
| ART should be started as soon as possible within 2 wk of initiating TB treatment, regardless of CD4 count (strong recommendation; low–moderate certainty in adults and very low certainty in children). | |
| Adjuvant steroids in TB meningitis and pericarditis | For TB meningitis, initiate corticosteroid therapy (dexamethasone or prednisolone) tapered over 6–8 wk (strong recommendation and moderate certainty of evidence). |
| Adjuvant steroids in TB meningitis and pericarditis | For TB pericarditis, corticosteroids may be used (conditional recommendation and very low certainty of evidence). |
Abbreviation: E, ethambutol; FDC, fixed dose combination; H, isoniazid; I, isoniazid; M, moxifloxacin; R, rifampin; Z, pyrazinamide.
Outcomes
Mortality in patients with TB in the critical care setting is high. In one systematic review, the average in-hospital mortality across 17 studies was 52.9%. One review article from a low TB-burden, high income country demonstrated a mortality of 33%. Predictors of mortality have been variable but include inadequate or delayed TB treatment, severe hypoxemia, need for mechanical ventilation and acute kidney injury. ,, Miliary TB, TB meningitis, multidrug resistant TB, and TB/HIV coinfection have also been associated with increased mortality.
Tuberculosis in the global intensive care unit
| Key Area | Summary |
|---|---|
| Severe presentations | Respiratory failure and ARDS are the most common presentations of critically ill patients with TB. Septic shock may also occur and can be a primary presenting feature. |
| Incidental diagnosis | In high-prevalence areas, TB may be detected incidentally in patients admitted to the ICU for other, unrelated reasons. |
| Diagnostic complexity | There is no single test to rule out TB. Diagnosis, especially of extrapulmonary TB, requires a combination of clinical judgment, imaging, histology, culture, and molecular tests. |
| Treatment timing | Early initiation of anti-TB therapy is strongly associated with improved outcomes and survival. |
Malaria
Malaria is a mosquito-borne parasitic disease that primarily affects red blood cells and is potentially life threatening. It is common in many LMIC countries in Africa, South and Central America, parts of Mexico, and large parts of Asia. It is caused by 6 species of Plasmodium : P falciparum , P vivax , P ovale curtisi , P ovale wallikeri , P malariae and P knowlesi . Of these 6, severe disease is primarily caused by P falciparum but P knowlesi and P vivax may occasionally also do so. P falciparum causes 99% of cases of malaria in Africa and about two-thirds of the cases in Southeast Asia. The vector for malaria is the female Anopheles mosquito. , The number of malaria cases in 2023 was estimated at 263 million, with Africa accounting for 94% of cases. The number of deaths was estimated at 597,000 (mortality rate 13.7 per 100,000 total population at risk), 95% of which occurred in Africa. Approximately 1% of P falciparum infections result in severe illness, again with almost all cases occurring in Africa. Children and pregnant women and nonimmune travelers to endemic areas are the most susceptible to severe malaria.
Clinical Presentation
P falciparum is the main cause of critical illness due to its capacity to generate high levels of parasitaemia, which occlude microvasculature, resulting in end-organ damage. The incubation period is approximately 10 to 15 days after a bite by an infected mosquito. Progression to severe malaria can be rapid, especially in vulnerable populations. Critical illness in adults may present as acute kidney injury, cerebral malaria, pulmonary edema/ARDS, severe anemia, coagulopathy, shock, and multiorgan failure. A pitfall in management of severe malaria is nonspecific presentation and late recognition. The presentation as a febrile illness with progressive severity can mimic many other conditions common in LMIC including typhoid fever, bacterial meningitis, viral encephalitis, dengue, TB, and rickettsial infections. , In addition, asymptomatic parasitaemia could occur in malaria endemic regions, which could confound diagnosis ( Table 4 ).
Table 4
Definitions and diagnostic criteria for severe falciparum malaria
Source WHO Guidelines for Malaria, 13 August 2025.
| Criterion | Definition/Diagnostic Threshold |
|---|---|
| Impaired consciousness | GCS <11 in adults or Blantyre Coma Score <3 in children. |
| Prostration | Generalized weakness such that the person is unable to sit, stand, or walk without assistance. |
| Multiple convulsions | More than 2 episodes within 24 h. |
| Acidosis | Base deficit > 8 mEq/L or plasma bicarbonate < 15 mmol/L or venous plasma lactate ≥5 mmol/L. Clinically manifests as rapid, deep, labored breathing (respiratory distress). |
| Hypoglycaemia | Blood or plasma glucose < 2.2 mmol/L (<40 mg/dL). |
| Severe malarial anemia |
Children (<12 y): Hb ≤ 5 g/dL or hematocrit ≤ 15% and parasite count > 10,000/μL.
Adults: Hb < 7 g/dL or hematocrit < 20% and parasite count > 10,000/μL. |
| Renal impairment | Plasma or serum creatinine >265 μmol/L (3 mg/dL) or blood urea >20 mmol/L. |
| Jaundice | Plasma or serum bilirubin > 50 μmol/L (3 mg/dL) and parasite count >100,000/μL. |
| Pulmonary edema | Radiological evidence or oxygen saturation <92% on room air with respiratory rate >30/min, often with chest indrawing and crepitations. |
| Significant bleeding | Recurrent or prolonged bleeding (eg, from nose, gums, and venepuncture sites), hematemesis, or melaena. |
| Shock |
Compensated: Capillary refill ≥3 s or temperature gradient in the limb without hypotension.
Decompensated: Systolic BP <70 mm Hg in children or <80 mm Hg in adults and signs of impaired perfusion (cool peripheries, prolonged capillary refill). |
| Hyperparasitaemia | P falciparum parasitaemia >10%. |
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