Four Years Since COVID-19 Day Zero: A Time to Evaluate Past and Future Pandemic Control Policies and Practices in Sub-Saharan Africa?

Four years after the first case of COVID-19, the world is still determining how best to prevent and control the long-term effects of SARS-CoV-2 infection. Non-pharmaceutical interventions (NPIs) were employed at the start of the pandemic as the only available options, prior to effective vaccines and antiviral agents. The World Health Organization recommended dual vaccination for 70% worldwide as the threshold for a return to "normal" community life. Immunization rates needed to increase in all global regions, irrespective of socioeconomic status, necessitating more equitable access. During the pandemic, wealthier countries hoarded vaccine supplies even when their citizens were immunized. This highlights the already enormous difficulties in healthcare provision faced by low-income sub-Saharan African countries, which remain at risk as industrialized nations have progressed to a post-pandemic era. Thus, in addition to redoubling vaccination efforts public health policymakers should consider ongoing and future use of NPIs. In this narrative account, we advocate that various NPI practices should not be shelved; rather, more research is needed to evaluate their impact in parallel with booster vaccination. This especially applies to so-called "long COVID". Lessons learned from implementing best practices in resource-limited settings should be incorporated into preparedness guidelines for future infectious disease outbreaks.

Integrating mental health screening into routine community maternal and child health activity: experience from Prevention of Mother-to-child HIV transmission (PMTCT) trial in Nigeria.

PURPOSE: Although the prevalence of mental health disorders in Nigeria is comparable to most developed countries, access to mental health care in Nigeria is limited. Improving access to care requires innovative approaches that deliver mental health interventions at the community level. The aim of this study was to determine the feasibility and acceptability of integrating mental health screening into an existing community-based program for prevention of mother-to-child transmission of HIV targeted at pregnant women and their male partners. METHODS: Pregnant women and their male partners from 117 churches enrolled in the healthy beginning initiative (HBI) in southeast Nigeria participated in the mental health screening project. Two members from each church were trained as church-based health advisors to administer the 12-item general health questionnaire. RESULTS: Ninety-three percent of the pregnant women and their male partners agreed to participate and fully completed the questionnaire. Overall, 21.7 % of the respondents scored above the threshold of 11 indicating significant psychological distress, with women having significantly higher scores than men. CONCLUSION: Mental health screening is feasible and well accepted among a cohort of pregnant women and their male partners. Church members can be trained as health advisors to administer mental health screening. Mental health interventions can be developed on the framework of the HBI.

Clinical predictors of bloodstream infections and mortality in hospitalized Malawian children.

BACKGROUND: In sub-Saharan Africa, bloodstream infections (BSI) are a major cause of pediatric mortality. Because of limited resources and facilities in these developing countries, treatment often must be based solely on clinical observations and patient history and includes the use of broad spectrum antimicrobials, a factor in the emergence of antibiotic resistance. METHODS: During July 28 through August 18, 1998 we analyzed clinical, epidemiologic and microbiologic data from a cohort of 225 hospitalized children in Malawi, Africa, to determine clinical indices associated with the presence/absence of BSI and/or mortality for use in settings with minimal microbiologic laboratory and intensive care facilities. RESULTS: BSI (n = 35 children) were associated with malnutrition, chronic cough, lethargy by history, lethargy on examination and oral thrush; 92% of children without these symptoms were BSI-negative. Mortality (21 of 173 children with known mortality status) was associated with malnutrition, lethargy on examination, prior receipt of antimalarials and acute decreased feeding. Of those with > or =2 of these indices 69% died; of those with <2 of the indices 94% survived. Infection with human immunodeficiency virus was not significantly related to either BSI or mortality status. CONCLUSIONS: Malnutrition, but not HIV, was strongly related to both BSI and mortality. Assessment of these BSI and mortality indices at hospital admission provides rapid, cost-free indication of which children are most/least in need of empiric antimicrobial therapy or intensive observation, thereby maximizing appropriate use of antimicrobials and limited facilities while minimizing inappropriate antimicrobial usage.

Antibiotic resistance and serotype distribution of Streptococcus pneumoniae colonizing rural Malawian children.

Nasopharyngeal swabs were taken from 906 Malawian children <5 years old visiting rural health clinics. Pneumococcal colonization was high, 84% among all children, and occurred early, 65% of it in children <3 months old. Among pneumococcal isolates 46% were nonsusceptible to trimethoprim-sulfamethoxazole, and 21% were nonsusceptible to penicillin. Trimethoprim-sulfamethoxazole use in the previous month was a risk factor for trimethoprim-sulfamethoxazole and penicillin nonsusceptibility. Forty-three percent of isolates were serotypes included in the 7-valent pneumococcal conjugate vaccine, and 37% were vaccine-related serotypes, particularly 6A and 19A.

Peripheral blood cell-specific cytokines in persons with untreated HIV infection in Malawi, Africa.

Human immunodeficiency virus (HIV) infection is the primary cause of morbidity and mortality in Malawi, Africa, because of its many effects on the immune system. Immune cells communicate through cytokines; therefore, we examined the relationships between HIV serostatus and cell-specific cytokine production for 40 asymptomatic, employed adults and 312 acutely ill, hospitalized patients in Malawi. We also measured the plasma HIV-1 RNA levels of 13 asymptomatic persons and 83 patients found to be HIV(+). We incubated peripheral whole blood with brefeldin-A +/- phorbol 12-myristate 13-acetate and ionomycin and then permeabilized, fixed, fluorescently stained, and examined the mononuclear cells with four-color, six-parameter flow cytometry. The percentage of lymphocytes expressing CD4 did not differ significantly between the HIV(+) and HIV(-) healthy adults (medians, 35.2 vs. 40.8%, respectively), but a wide array of cytokine parameters were lower in the HIV(+) than in the HIV(-) asymptomatic persons, for example, median percentages of T cells producing induced interleukin 2 (IL-2) (8.7 vs. 16.5%, respectively) and spontaneously producing IL-6 (0.7 vs. 11.0%, respectively). Also, four T cell parameters reflecting type 2-to-type 1 cytokine balances (T2/T1) were higher in the HIV(+), versus HIV(-), asymptomatic persons. Unlike the healthy adults, for patients with mycobacteremia/fungemia or malaria, the HIV(+) patients had higher median percentages of T cells and CD8(+) T cells producing induced interferon gamma than did the HIV(-) PATIENTS: For both asymptomatic and acutely ill persons, HIV-1 plasma levels were positively correlated with T2/T1 parameters. Cell-specific cytokine effects of HIV infection may precede measurable effects on CD4 expression. Cytokine therapies, even beyond periodic administration of IL-2, may improve the responses of HIV-infected persons to both HIV and coinfections.

Clinical and immune impact of Mycobacterium bovis BCG vaccination scarring.

The World Health Organization recommends Mycobacterium bovis BCG vaccination in areas of high tuberculosis prevalence. BCG's clinical and immune effects, not necessarily Mycobacterium tuberculosis specific, are unclear. BCG vaccine scarring often is used as a surrogate marker of vaccination or of effective vaccination. We evaluated BCG scarring status in relation to clinical findings and outcome in 700 hospitalized Malawians, of whom 32 had M. tuberculosis bloodstream infections (BSI) (10 of whom had cellular immune studies done) and of whom 48 were infants <6 months old and therefore recently vaccinated (19 of whom had immune studies). In the patients >/=6 months old, scarring was not related to the presence of pulmonary symptoms (35 versus 30%), chronic cough or fever, mortality, or M. tuberculosis BSI. In M. tuberculosis BSI patients, scarring was unrelated to mortality, vital signs, or clinical symptoms but those with scarring had higher proportions of memory and activated T cells and more type 2-skewed cytokine profiles. Infants with either BCG scarring (n = 10) or BCG lesional inflammation (n = 5) had no symptoms of sepsis, but 18 of 33 infants without BCG vaccination lesions did. Those with BCG lesions had localized infections more often than did those without BCG lesions. These infants also had lower median percentages of lymphocytes spontaneously making interleukin-4 (IL-4) or tumor necrosis factor alpha (TNF-alpha) and lower ratios of T cells spontaneously making IL-4 to T cells making IL-6. Thus, we found that, in older patients, BCG vaccine scarring was not associated with M. tuberculosis-specific or nonspecific clinical protection. Those with M. tuberculosis BSI and scarring had immune findings suggesting previous M. tuberculosis antigen exposure and induction of a type 2 cytokine pattern with acute reexposure. It is unlikely that this type 2 pattern would be protective against mycobacteria, which require a type 1 response for effective containment. In infants <6 months old, recent BCG vaccination was associated with a non-M. tuberculosis-specific, anti-inflammatory cytokine profile. That the vaccinated infants had a greater frequency of localized infections and lesser frequency of sepsis symptoms suggests that this postvaccination cytokine pattern may provide some non-M. tuberculosis-specific clinical benefits.

Spontaneous cytokine production and its effect on induced production.

Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) by peripheral-blood B lymphocytes, T cells, CD8(-) T cells, CD8(+) T cells, CD3(-) CD16/56(+) lymphocytes (natural killer [NK] cells), CD3(+) CD16/56(+) lymphocytes (natural T [NT] cells), and/or monocytes of 316 acutely ill hospitalized persons and 62 healthy adults in Malawi, Africa. We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-alpha production occurred most frequently, followed in descending order by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-alpha; for 12 of these patients, TNF-alpha was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-alpha and IFN-gamma, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.

Vitamin A levels and immunity in humans.

In animal studies, vitamin A deficiency induces a shift from type 2 (humoral) to type 1 (cellular) cytokines; there are no similar data for humans. Control of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis infections requires type 1 cytokine (cellular) immunity. These infections and vitamin A deficiency are highly prevalent in Africa. We therefore examined the interactions among serum vitamin A levels, immune parameters, HIV infection status, Mycobacterium bovis BCG vaccine scarring (as an indicator of a type 1 cytokine profile), and clinical findings for 70 hospitalized children in Malawi, Africa. Directly conjugated monoclonal antibodies and flow cytometry were used to assess cell-specific cytokine production by peripheral blood monocytes and lymphocyte subpopulations. The statistical techniques employed included nonparametric statistics and logistic regression analyses. Thirty percent of the participants had severe vitamin A deficiency (<10 microg/dl), 34% had moderate deficiency (10 to <20 microg/dl), and 36% had normal levels (> or = 20 microg/dl). Vitamin A levels were lower for HIV-positive than for HIV-negative children (median, 10 and 17 microg/dl, respectively). Vitamin A-deficient children (<20 microg/dl) were more likely than non-vitamin A-deficient children to have higher proportions of natural killer (NK) cells (median, 8.3 and 5.2%, respectively) and lower ratios of interleukin-10-producing monocytes to tumor necrosis factor alpha-producing monocytes after induction (median, 1.0 and 2.3, respectively). Vitamin A-deficient children were also more likely than non-vitamin A-deficient children to exhibit respiratory symptoms (47% versus 12%) and visible BCG vaccine scars (83% versus 48%), which are indicative of a type 1 response to vaccination. Vitamin A status did not vary with gender, age, incidence of malaria parasitemia, blood culture positivity, or rates of mortality (6% of vitamin A-deficient children died versus 20% of non-vitamin A-deficient children). Lower vitamin A levels were associated with a relative type 1 cytokine dominance and proportionately more NK cells, both of which may be somewhat beneficial to persons who are exposed to HIV, M. tuberculosis, or other type 1 pathogens.

Demographic and immune correlates of human herpesvirus 8 seropositivity in Malawi, Africa.

BACKGROUND: In the USA, human herpesvirus 8 (HHV-8) is associated with Kaposi's sarcoma (KS) and HIV infection. We examined HHV-8 seroprevalence in a Malawian cohort, and assessed its relationship with HIV, KS, demographic characteristics, and immune findings. METHODS: In 1997 and 1998, blood samples were obtained from 272 hospitalized Malawian patients, for whom demographic information was obtained, and 24 healthy volunteers without demographic data. We used enzyme immunoassays to assess seroprevalence and antibody titers to peptide antigens derived from HHV-8 K8.1 and ORF65-encoded proteins. Intracellular cytokines and cell surface antigens were assessed with four-color flow cytometry. Data were analyzed using non-parametric univariate and regression analytic techniques. RESULTS: The rates of HHV-8 seroprevalence to either or both HHV-8 peptides were 67% for the patients and 54% for the healthy volunteers. Seroprevalence increased with patients' age (P<0.001) but was not associated with HIV status, percentage of lymphocytes expressing CD4, or KS (n=10). Seropositive females had lower antibody titers to both peptides than did males (medians: 455 versus 1361 for K8.1, P<0.001; and 268 versus 405 for ORF65, P=0.044). For the healthy volunteers, the percentage of CD8+ cells producing IFN-gamma after stimulation was significantly lower in ORF65-specific antibody-positive persons (medians: 24% versus 57%, P=0.008). CONCLUSIONS: In Malawi, HHV-8 is endemic and is not associated with HIV infection or HIV severity. Seroprevalence rates increase in childhood, and, most steeply in adolescence. Titers are higher in seropositive males than in sero-positive females. The immune effects of HHV-8 in healthy adults are consistent with chronic inhibition of type 1 cytotoxic T-cell responsiveness, independent of HIV status.